Publications by authors named "Mercè Boada"

156 Publications

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease: A randomized, placebo-controlled, phase 3 clinical trial (MINDSET).

Alzheimers Dement (N Y) 2021 31;7(1):e12136. Epub 2021 May 31.

Chambers-Grundy Center for Transformative Neuroscience Department of Brain Health, School of Integrated Health Sciences University of Nevada Las Vegas (UNLV) Las Vegas Nevada USA.

Introduction: A previous phase 2b study supported the use of the 5-HT6 receptor antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this hypothesis.

Methods: MINDSET was a global, double-blind, randomized, placebo-controlled trial in 1315 mild-to-moderate AD dementia patients on stable donepezil. Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co-primary endpoints were change from baseline to week 24 on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL).

Results: There were no statistically significant differences between intepirdine and placebo groups (adjusted mean [95% confidence interval]) on the co-primary endpoints ADAS-Cog (-0.36 [-0.95, 0.22],  = 0.2249) and ADCS-ADL (-0.09 [-0.90, 0.72],  = 0.8260). Intepirdine demonstrated a favorable safety profile similar to placebo.

Discussion: Intepirdine as adjunctive therapy to donepezil did not produce statistical improvement over placebo on cognition or activities of daily living in mild-to-moderate AD dementia patients.
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http://dx.doi.org/10.1002/trc2.12136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165732PMC
May 2021

[Teleconsultation in a coloproctology unit during the COVID-19 pandemic. Preliminary results].

Cir Esp 2021 May 8;99(5):361-367. Epub 2020 Jul 8.

Hospital Universitari Mútua Terrassa, Tarrasa, España.

Introduction: During the state of alarm established in Spain due to the COVID-19 pandemic, most of the face-to-face outpatient consultations were cancelled and a telephone consultation was established to follow up coloproctological patients. The objective of this study was to analyse the efficacy of telemedicine (by telephone) in monitoring patients in a coloproctology unit, in the context of the COVID-19 pandemic.

Method: Prospective descriptive study of consecutive patients in a single centre. The result of the teleconsultation was classified as discharge, resolved visit or reprogramming and was analysed by different diagnostic groups.

Results: From March 19th to April 17th, 2020, the teleconsultation of 190 patients was carried out. The response rate was 94.2% (179). The diagnostic categories of the patients attended were: 51 (26.9%) colorectal neoplasia, 48 (25.3%) proctological pathology, 72 (37.9%) pelvic floor dysfunctions and 19 (10%) other benign pathologies. 105 (55.26%) could be recited as if they had come in person. Eleven (5.8%) patients were discharged. No significant differences were found between the different diagnostic categories and the resolution of the teleconsultation. The reasons for reprogramming are analyzed in the study.

Conclusion: In the context of a pandemic, teleconsultation has allowed 61% of follow-up visits to be definitively solved, avoiding the reprogramming of 116 patients. The new social and health paradigm after the pandemic will require a rethinking of our healthcare model, and in many aspects, telemedicine can offer tools for this.
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http://dx.doi.org/10.1016/j.ciresp.2020.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342026PMC
May 2021

The role of sex and gender in the selection of Alzheimer patients for clinical trial pre-screening.

Alzheimers Res Ther 2021 05 5;13(1):95. Epub 2021 May 5.

Research Center and Memory Clinic. Fundació ACE. Institut Català de Neurociències Aplicades. Universitat Internacional de Catalunya, Gran Vía de Carles III, 85 BIS, 08028, Barcelona, Spain.

Background: Alzheimer disease (AD) is a progressive neurodegenerative disorder affecting the elderly with a prevalence of 7.1% in women and 3.3% in men. Sex-related patterns have been reported in prognosis, biomarker status, and risk factors. Despite this, the interaction of sex has received limited attention, with AD trials persistently recruiting lower numbers of women than the population distribution and a lack of information on the sex-disaggregated effects of anti-dementia therapies. This is the first study aiming to identify the role of sex in the selection for screening in AD clinical trials.

Methods: This cross-sectional study provides a comprehensive analysis of screening eligibility according to a set of pre-selection criteria currently applied at Fundació ACE memory clinic for a more efficient trial screening process. A cohort of 6667 women and 2926 men diagnosed with AD dementia (55%) or mild cognitive impairment (45%) was analyzed. We also assessed the frequencies of men and women effectively screened for trial enrolment over a period of 10 years. Additionally, data from AddNeuroMed study was used to explore trends in eligibility based on the education criteria.

Results: Women showed a significantly lower chance of being eligible for screening than men (OR = 1.26; p < 0.01). This imbalance was confirmed by a lower frequency of women screened for enrolment compared to the study population (63.0% vs. 69.5%). Education was revealed as the key criterion contributing to this unbalance, with men showing over twice the chance of being screened compared with women (OR = 2.25, p < 0.01). Education-based differences were greater in earlier born patients, but the gap narrowed and achieved balance with increasing year of birth. This observation was replicated using data from other European populations included in AddNeuroMed study. Comorbidity was the most limiting criterion with sex differences in frequencies and significant discrimination against the selection of men (OR = 0.86, p < 0.01).

Conclusions: The large number of low-educated elderly women with AD demands for a sex-focused approach in clinical research. New assessment tools insensitive to education level should be developed to enable a proportional representation of women. Although this gender education gap is mostly inexistent in developed countries, economic or cultural factors may lead to different scenarios in other regions. Overlooking the impact of sex may lead to a handicap in AD research with a direct adverse impact on women's health.
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http://dx.doi.org/10.1186/s13195-021-00833-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098013PMC
May 2021

From Face-to-Face to Home-to-Home: Validity of a Teleneuropsychological Battery.

J Alzheimers Dis 2021 Apr 28. Epub 2021 Apr 28.

Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya - Barcelona, Spain.

Background: Over the last decade, teleneuropsychology has increased substantially. There is a need for valid neuropsychological batteries to be administered home-to-home. Since 2006, the neuropsychological battery of Fundació ACE (NBACE) has been administered face-to-face in our clinical settings. Recently, we adapted the NBACE for teleneuropsychology use to be administered home-to-home (NBACEtn).

Objective: The aims of the present study are: 1) to determine the home-to-home NBACE equivalence compared to its original face-to-face version; and 2) to examine home-to-home NBACE discriminant capacity by differentiating among cognitively healthy, mild cognitive impairment, or mild dementia subjects and comparing it with the face-to-face version.

Methods: Data from 338 individuals assessed home-to-home (NBACEtn) were contrasted with 7,990 participants assessed with its face-to-face version (NBACE). Exploratory and confirmatory factorial structure, and invariance analysis of the two versions of the battery were performed.

Results: Exploratory and confirmatory factor analysis supported the four-factor model (attention, memory, executive, and visuospatial/constructional functions). Configural, metric, and scalar measurement invariance was found between home-to-home and face-to-face NBACE versions. Significant differences in most of the neuropsychological variables assessed were observed between the three clinical groups in both versions of administration. No differences were found between the technological devices used by participants (computer or tablet and mobile devices).

Conclusion: For the first time, invariance analysis findings were addressed by determining a teleneuropsychological battery's equivalence in comparison with its face-to-face version. This study amplifies the neuropsychological assessment's applicability using a home-to-home format, maintaining the original measure's structure, interpretability, and discriminant capacity.
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http://dx.doi.org/10.3233/JAD-201389DOI Listing
April 2021

Nanomedicine-based technologies and novel biomarkers for the diagnosis and treatment of Alzheimer's disease: from current to future challenges.

J Nanobiotechnology 2021 Apr 29;19(1):122. Epub 2021 Apr 29.

Research Center and Memory Clinic, Fundació ACE. Institut Català de Neurociències Aplicades, International University of Catalunya (UIC), C/Marquès de Sentmenat, 57, 08029, Barcelona, Spain.

Increasing life expectancy has led to an aging population, which has consequently increased the prevalence of dementia. Alzheimer's disease (AD), the most common form of dementia worldwide, is estimated to make up 50-80% of all cases. AD cases are expected to reach 131 million by 2050, and this increasing prevalence will critically burden economies and health systems in the next decades. There is currently no treatment that can stop or reverse disease progression. In addition, the late diagnosis of AD constitutes a major obstacle to effective disease management. Therefore, improved diagnostic tools and new treatments for AD are urgently needed. In this review, we investigate and describe both well-established and recently discovered AD biomarkers that could potentially be used to detect AD at early stages and allow the monitoring of disease progression. Proteins such as NfL, MMPs, p-tau217, YKL-40, SNAP-25, VCAM-1, and Ng / BACE are some of the most promising biomarkers because of their successful use as diagnostic tools. In addition, we explore the most recent molecular strategies for an AD therapeutic approach and nanomedicine-based technologies, used to both target drugs to the brain and serve as devices for tracking disease progression diagnostic biomarkers. State-of-the-art nanoparticles, such as polymeric, lipid, and metal-based, are being widely investigated for their potential to improve the effectiveness of both conventional drugs and novel compounds for treating AD. The most recent studies on these nanodevices are deeply explained and discussed in this review.
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http://dx.doi.org/10.1186/s12951-021-00864-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086346PMC
April 2021

Identification of undiagnosed dementia cases using a web-based pre-screening tool: The MOPEAD project.

Alzheimers Dement 2021 Apr 15. Epub 2021 Apr 15.

Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.

Introduction: Innovative patient engagement models are required to identify people with prodromal and mild Alzheimer's disease who are "hidden" in their communities and not normally found in a memory clinic setting.

Methods: A marketing campaign and a web-based pre-screening tool were used to identify individuals at risk of dementia in five European countries. Harmonized clinical evaluation of these patients was performed in participating memory clinics within the MOPEAD project.

Results: A total of 1487 individuals completed the pre-screening, with 547 of them found to be at risk of dementia (36.8%). Among the subset of 91 patients with a positive pre-screening result that underwent full clinical evaluation, 49 (53.8%) were diagnosed with either mild cognitive impairment or Alzheimer's disease.

Conclusion: This novel web-based pre-screening tool showed to be a valid strategy to identify undiagnosed people with cognitive impairment.
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http://dx.doi.org/10.1002/alz.12297DOI Listing
April 2021

Early detection of amyloid load using F-florbetaben PET.

Alzheimers Res Ther 2021 03 27;13(1):67. Epub 2021 Mar 27.

Fundació ACE Institut Català de Neurociències Aplicades, Research Center and Memory Unit - Universitat Internacional de Catalunya (UIC), Barcelona, Spain.

Background: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using F-florbetaben PET. Quantitative thresholds for the early (SUVR) and established (SUVR) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition.

Methods: The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition ("gray zone"), and subjects with established Aβ pathology.

Results: SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology.

Conclusions: This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention.

Trial Registration: Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).
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http://dx.doi.org/10.1186/s13195-021-00807-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005243PMC
March 2021

Neuropsychiatric profiles and conversion to dementia in mild cognitive impairment, a latent class analysis.

Sci Rep 2021 Mar 19;11(1):6448. Epub 2021 Mar 19.

Research Center and Memory Clinic, Fundació ACE, Barcelona Alzheimer Treatment and Research Centre, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC) - Barcelona, Gran Vía Carles III, 85 bis, bajos, 08028, Barcelona, Spain.

Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment (MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI.
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http://dx.doi.org/10.1038/s41598-021-83126-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979780PMC
March 2021

General practitioners' attitude toward early and pre-dementia diagnosis of AD in five European countries-A MOPEAD project survey.

Alzheimers Dement (Amst) 2021 23;13(1):e12130. Epub 2021 Feb 23.

Department of Psychiatry University of Cologne Faculty of Medicine and University Hospital Cologne Cologne Germany.

Introduction: General practitioners (GPs) play a key role in early identification of dementia, yet diagnosis is often missed or delayed in primary care. As part of the multinational Models of Patient Engagement for Alzheimer's Disease project, we assess GPs' attitude toward early and pre-dementia diagnosis of AD and explore barriers to early diagnosis.

Methods: Our survey covered general attitude toward early diagnosis, diagnostic procedures, resources, and opinion on present and future treatment options across five European countries.

Results: In total 343 GPs completed the survey; 74% of GPs indicated that an early diagnosis is valuable. There were country-specific differences in GPs' perceptions of reimbursement and time available for the patient. If a drug were available to slow down the progression of AD, 59% of the GPs would change their implementation of early diagnosis.

Discussion: Our findings provide insight into GPs' attitudes by exploring differences in perception and management of early diagnosis.
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http://dx.doi.org/10.1002/dad2.12130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901232PMC
February 2021

Long runs of homozygosity are associated with Alzheimer's disease.

Transl Psychiatry 2021 Feb 24;11(1):142. Epub 2021 Feb 24.

Dep. of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
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http://dx.doi.org/10.1038/s41398-020-01145-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904832PMC
February 2021

Biomarker-Based Risk Prediction of Alzheimer's Disease Dementia in Mild Cognitive Impairment: Psychosocial, Ethical, and Legal Aspects.

J Alzheimers Dis 2021 ;80(2):601-617

Cologne Center for Ethics, Rights, Economics, and Social Sciences of Health (ceres), University of Cologne, Cologne, Germany.

Background: Today, a growing number of individuals with mild cognitive impairment (MCI) wish to assess their risk of developing Alzheimer's disease (AD) dementia. The expectations as well as the effects on quality of life (QoL) in MCI patients and their close others through biomarker-based dementia risk estimation are not well studied.

Objective: The PreDADQoL project aims at providing empirical data on effects of such prediction on QoL and at developing an ethical and legal framework of biomarker-based dementia risk estimation in MCI.

Methods: In the empirical study, 100 MCI-patients and their close others will be recruited from two sites (Germany and Spain). They receive standardized counselling on cerebrospinal fluid (CSF) biomarker-based prediction of AD dementia and a risk disclosure based on their AD biomarker status. A mixed methods approach will be applied to assess outcomes.

Results: The pilot-study yielded a specification of the research topics and newly developed questionnaires for the main assessment. Within this binational quantitative and qualitative study, data on attitudes and expectations toward AD risk prediction, QoL, risk communication, coping strategies, mental health, lifestyle changes, and healthcare resource utilization will be obtained. Together with the normative part of the project, an empirically informed ethical and legal framework for biomarker-based dementia risk estimation will be developed.

Conclusion: The empirical research of the PreDADQoL study together with the ethical and legal considerations and implications will help to improve the process of counselling and risk disclosure and thereby positively affect QoL and health of MCI-patients and their close others in the context of biomarker-based dementia risk estimation.
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http://dx.doi.org/10.3233/JAD-200484DOI Listing
January 2021

Interaction of neuropsychiatric symptoms with APOE ε4 and conversion to dementia in MCI patients in a Memory Clinic.

Sci Rep 2020 11 18;10(1):20058. Epub 2020 Nov 18.

Research Center and Memory Clinic, Fundació ACE Institut Català de Neurociències Aplicades - Universitat Internacional de Catalunya (UIC), Gran Via Carles III, 85 bis., 08028, Barcelona, Spain.

To date, very few studies have been focused on the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE ε4 on the conversion to dementia in patients with Mild Cognitive Impairment patients (MCI), and none has been based in a clinical setting. The objective of the study is to determine the predictive value of additive and multiplicative interactions of NPS and APOE ε4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic. 1512 patients (aged 60 and older) with prevalent MCI were followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated. Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ε4 carrier status were obtained, significantly increasing the hazard ratios of incident dementia (HR range 1.3-2.03). Synergistic interactions between NPS and APOE ε4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.
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http://dx.doi.org/10.1038/s41598-020-77023-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674479PMC
November 2020

Cognitive and Neuropsychiatric Manifestations of COVID-19 and Effects on Elderly Individuals With Dementia.

Front Aging Neurosci 2020 26;12:588872. Epub 2020 Oct 26.

Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide and has had unprecedented effects in healthcare systems, economies and society. COVID-19 clinical presentation primarily affects the respiratory system causing bilateral pneumonia, but it is increasingly being recognized as a systemic disease, with neurologic manifestations reported in patients with mild symptoms but, most frequently, in those in a severe condition. Elderly individuals are at high risk of developing severe forms of COVID-19 due to factors associated with aging and a higher prevalence of medical comorbidities and, therefore, they are more vulnerable to possible lasting neuropsychiatric and cognitive impairments. Several reports have described insomnia, depressed mood, anxiety, post-traumatic stress disorder and cognitive impairment in a proportion of patients after discharge from the hospital. The potential mechanisms underlying these symptoms are not fully understood but are probably multifactorial, involving direct neurotrophic effect of SARS-CoV-2, consequences of long intensive care unit stays, the use of mechanical ventilation and sedative drugs, brain hypoxia, systemic inflammation, secondary effects of medications used to treat COVID-19 and dysfunction of peripheral organs. Chronic diseases such as dementia are a particular concern not only because they are associated with higher rates of hospitalization and mortality but also because COVID-19 further exacerbates the vulnerability of those with cognitive impairment. In patients with dementia, COVID-19 frequently has an atypical presentation with mental status changes complicating the early identification of cases. COVID-19 has had a dramatical impact in long-term care facilities, where rates of infection and mortality have been very high. Community measures implemented to slow the spread of the virus have forced to social distancing and cancelation of cognitive stimulation programs, which may have contributed to generate loneliness, behavioral symptoms and worsening of cognition in patients with dementia. COVID-19 has impacted the functioning of Memory Clinics, research programs and clinical trials in the Alzheimer's field, triggering the implementation of telemedicine. COVID-19 survivors should be periodically evaluated with comprehensive cognitive and neuropsychiatric assessments, and specific mental health and cognitive rehabilitation programs should be provided for those suffering long-term cognitive and psychiatric sequelae.
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http://dx.doi.org/10.3389/fnagi.2020.588872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649130PMC
October 2020

Heterozygous APOE Christchurch in familial Alzheimer's disease without mutations in other Mendelian genes.

Neuropathol Appl Neurobiol 2021 Jun 5;47(4):579-582. Epub 2020 Nov 5.

Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.

We present the clinical and neuropathological findings of a patient with early onset Alzheimer's dementia (AD), heterozygous carrier of the rare Apolipoprotein E Christchurch (APOEch) variant. The patient did not harbor any pathogenic mutation in known Mendelian genes related to AD or other neurodegenerative disorders. A sibling of this patient, also carrying the APOEch variant, developed AD at the age of 66 years old. Our data suggest a possible deleterious effect of this variant, which contrast with the protective role that has been previously shown in a subject homozygous for the APOEch with he Paisa PSEN1 mutation.
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http://dx.doi.org/10.1111/nan.12670DOI Listing
June 2021

Subtle executive deficits are associated with higher brain amyloid burden and lower cortical volume in subjective cognitive decline: the FACEHBI cohort.

Sci Rep 2020 10 20;10(1):17721. Epub 2020 Oct 20.

Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, C/ Gran Via de Carles III, 85 bis, 08028, Barcelona, Spain.

To determine whether lower performance on executive function tests in subjective cognitive decline (SCD) individuals are associated with higher levels of brain amyloid beta (Aβ) deposition and regional volumetric reduction in areas of interest for Alzheimer's disease (AD). 195 individuals with SCD from the FACEHBI study were assessed with a neuropsychological battery that included the following nine executive function tests: Trail Making Test A and B (TMTA, TMTB), the Rule Shift Cards subtest of BADS, the Automatic Inhibition subtest of the Syndrom Kurz Test (AI-SKT), Digit Span Backwards and Similarities from WAIS-III, and the letter, semantic, and verb fluency tests. All subjects underwent an 18F-Florbetaben positron emission tomography (FBB-PET) scan to measure global standard uptake value ratio (SUVR), and a magnetic resonance imaging (MRI). A multiple regression analysis, adjusted for age, was carried out to explore the association between global SUVR and performance on executive tests. Then, on those tests significantly associated with amyloid burden, a voxel-based morphometry (VBM) analysis was carried out to explore their correlates with grey matter volume. Multiple regression analysis revealed a statistically significant association between Aβ deposition and performance on one of the executive tests (the AI-SKT). Moreover, VBM analysis showed worse AI-SKT scores were related to lower volume in bilateral hippocampus and left inferior frontal regions. In conclusion, in SCD individuals, worse automatic inhibition ability has been found related to higher cerebral Aβ deposition and lower volume in the hippocampus and frontal regions. Thus, our results may contribute to the early detection of AD in individuals with SCD.
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http://dx.doi.org/10.1038/s41598-020-74704-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576802PMC
October 2020

Association of lysophosphatidic acids with cerebrospinal fluid biomarkers and progression to Alzheimer's disease.

Alzheimers Res Ther 2020 10 2;12(1):124. Epub 2020 Oct 2.

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.

Background: Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer's disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD.

Methods: The current study was performed on cerebrospinal fluid (CSF) and plasma samples of 182 MCI patients from two independent cohorts. We profiled LPA-derived metabolites using liquid chromatography-mass spectrometry. We evaluated the association of LPAs with CSF biomarkers of AD, Aβ-42, p-tau, and total tau levels overall and stratified by APOE genotype and with MCI to AD progression.

Results: Five LPAs (C16:0, C16:1, C22:4, C22:6, and isomer-LPA C22:5) showed significant positive association with CSF biomarkers of AD, Aβ-42, p-tau, and total tau, while LPA C14:0 and C20:1 associated only with Aβ-42 and alkyl-LPA C18:1, and LPA C20:1 associated with tau pathology biomarkers. Association of cyclic-LPA C16:0 and two LPAs (C20:4, C22:4) with Aβ-42 levels was found only in APOE ε4 carriers. Furthermore, LPA C16:0 and C16:1 also showed association with MCI to AD dementia progression, but results did not replicate in an independent cohort.

Conclusions: Our findings provide evidence that LPAs may contribute to early AD pathogenesis. Future studies are needed to determine whether LPAs play a role in upstream of AD pathology or are downstream markers of neurodegeneration.
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http://dx.doi.org/10.1186/s13195-020-00680-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532619PMC
October 2020

Managing Clinical Trials for Alzheimer's Disease During the COVID-19 Crisis: Experience at Fundació ACE in Barcelona, Spain.

J Alzheimers Dis 2020 ;77(4):1805-1813

Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.

Background: The COVID-19 pandemic has brought great disruption to health systems worldwide. This affected ongoing clinical research, particularly among those most vulnerable to the pandemic, like dementia patients. Fundació ACE is a research center and memory clinic based in Barcelona, Spain, one of the hardest-hit countries.

Objective: To describe the ad-hoc strategic plan developed to cope with this crisis and to share its outcomes.

Methods: We describe participants' clinical and demographic features. Additionally, we explain our strategic plan aimed at minimizing the impact on clinical trial research activities, which included SARS-CoV-2 RT-PCR and IgG serological tests to all participants and personnel. The outcomes of the plan are described in terms of observed safety events and drop-outs during the study period.

Results: A total of 130 patients were participating in 16 active clinical trials in Fundació ACE when the lockdown was established. During the confinement, we performed 1018 calls to the participants, which led to identify adverse events in 26 and COVID-19 symptoms in 6. A total of 83 patients (64%) could restart on-site visits as early as May 11, 2020. All SARS-CoV-2 RT-PCR diagnostic tests performed before on-site visits were negative and only three IgG serological tests were positive. Throughout the study period, we only observed one drop-out, due to an adverse event unrelated to COVID-19.

Discussion: The plan implemented by Fundació ACE was able to preserve safety and integrity of ongoing clinical trials. We must use the lessons learned from the pandemic and design crisis-proof protocols for clinical trials.
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http://dx.doi.org/10.3233/JAD-200750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683041PMC
October 2020

, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

Neurology 2020 12 17;95(24):e3288-e3302. Epub 2020 Sep 17.

From the Institute of Neurology (B.C., D.A.K., J.H., P.A.L., R.F.), School of Pharmacy (C.M.), and UCL Movement Disorders Centre (J.H.), University College London; School of Pharmacy (C.M., P.A.L.), University of Reading, Whiteknights; Neurogenetics Laboratory (M.B.-Q., C.W., J.M.P.), National Hospital for Neurology and Neurosurgery, London, UK; Aptima Clinic (Miquel Aguilar), Terrassa; Memory Disorders Unit, Department of Neurology (I.A., M.D.-F., P.P.), University Hospital Mutua de Terrassa, Barcelona; Hospital Universitario Central de Asturias (V.A., M.M.-G.), Oviedo, Spain; NORMENT (O.A.), Institute of Clinical Medicine, University of Oslo, Norway; Regional Neurogenetic Centre (Maria Anfossi, Livia Bernardi, A.C.B., M.E.C., Chiara Cupidi, F.F., Maura Gallo, R.M., N.S.), ASPCZ, Lamezia Terme; Department of Neuroscience, Psychology, Drug Research and Child Health (S.B., B.N., I.P., S.S.), University of Florence; Molecular Markers Laboratory (Luisa Benussi, Giuliano Binetti, R.G.), IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience (D.B.), University of Sheffield, UK; Research Center and Memory Clinic (M.B., I.H., S.M.-G., Agustín Ruiz), Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain; Centre for Neurodegenerative Disorders (B.B., A.P.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Department of Clinical Neurosciences (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neurology (Geir Bråthen, S.B.S.), University Hospital of Trondheim, Norway; Dept NVS, Division of Neurogeriatrics (H.-H.C., C.G., B.K., L.Ö.), Karolinska Institutet, Bioclinicum Solna, Sweden; Department of Neurology (J.C., O.D.-I., I.I.-G., A.L.), IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain; Anne Rowling Regenerative Neurology Clinic (S.C., G.J.T.H., S.P.) and Centre for Clinical Brain Sciences (S.P.), University of Edinburgh, UK; NeuroGenomics and Informatics, Department of Psychiatry (Carlos Cruchaga), Washington University, St. Louis, MO; Cognitive Impairment Center (M.E.D.B., Maurizio Gallucci) and Immunohematology and Transfusional Medicine Service (E.D., A.V.), Local Health Authority n.2 Marca Trevigiana, Treviso, Italy; Department of Psychiatry and Psychotherapy (J.D.-S., C.R.), School of Medicine, Technical University of Munich, Germany; Department of Neurology (D.F., M.G.K.) and Clinical Institute of Medical Genetics (A.M., B.P.), University Medical Center Ljubljana, Slovenia; Dino Ferrari Center (D.G., Elio Scarpini, M.S.), University of Milan, Italy; Cognitive Neuroscience Lab, Think and Speak Lab (J.H.G.), Shirley Ryan Ability Lab, Chicago, IL; Department of Pathology and Laboratory Medicine (Murray Grossman, EunRan Suh, J.Q.T., V.M.V.D.), Center for Neurodegenerative Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia; UCL Dementia Research Institute (J.H.), London; Reta Lila Weston Institute (J.H.), UCL Queen Square Institute of Neurology, UK; Institute for Advanced Study (J.H.), The Hong Kong University of Science and Technology, China; Royal Edinburgh Hospital (G.J.T.H.), UK; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (E.D.H.), Columbia University, New York, NY; Department of Neurology, Memory and Aging Center (A.K., B.M., J.Y.), University of California, San Francisco; UCL Genomics (M.K., G.K.M., Y.P.), UCL Great Ormond Street Institute of Child Health, London, UK; Geriatric Center Frullone ASL Napoli 1 Centro (G.M.), Napoli, Italy; Department of Neurology (M.O.M., J.v.R., J.C.V.S.), Erasmus Medical Center, Rotterdam, the Netherlands; Rona Holdings (P.M.), Silicon Valley, CA; Newcastle Brain Tissue Resource, Institute of Neuroscience (C.M.M.), Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK; Department of Neurology (C.N.), Skåne University Hospital, Malmö, Sweden; Fondazione Policlinico Universitario A. Gemelli IRCCS (V.N.), Rome, Italy; Division of Neuroscience & Experimental Psychology (S.P.-B., A.M.T.R., S.R., J.C.T.), University of Manchester, UK; Amsterdam University Medical Center (Y.A.L.P.), VU University Medical Center, the Netherlands; Cardiovascular Research Unit (A.A.P.), IRCCS Multimedica, Milan; Neurology I, Department of Neuroscience (I.R., Elisa Rubino), University of Torino; NeurOMICS laboratory (G.M., Antonella Rendina, E.V.), Institute of Biochemistry and Cell Biology (IBBC), CNR Napoli, Italy; Manchester Centre for Clinical Neurosciences (A.M.T.R., J.S., J.C.T.), Salford Royal NHS Trust, Manchester, UK; Tanz Centre for Research in Neurodegenerative Diseases (Ekaterina Rogaeva), University of Toronto, Canada; Department of Biotechnology (B.R.), Jožef Stefan Institute, Ljubljana, Slovenia; Division of Neurology V and Neuropathology (G.R., F.T.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Hospital Clínic of Barcelona, Spain; Clinical Memory Research Unit, Department of Clinical Sciences Malmö (C.N., A.F.S.), and Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund (M.L.W.), Lund University, Sweden; Neurodegenerative Brain Diseases Group (J.V.d.Z., C.V.B.), Center for Molecular Neurology, VIB, Antwerp, Belgium; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (V.E.-P.), Division of Psychological Medicine and Clinical Neurosciences and Dementia Research Institute, Cardiff University, UK; Instituto de Investigación Sanitaria del Principado de Asturias (V.A.), Oviedo, Asturias; Fundació per la Recerca Biomèdica i Social Mútua Terrassa (I.A., M.D.-F., P.P.), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (M.B., J.C., O.D.-I., I.H., I.I.-G., A.L., S.M.-G., Agustín Ruiz), Instituto de Salud Carlos III, Madrid, Spain; MRC Cognition and Brain Sciences Unit (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neuromedicine and Movement Science (Geir Bråthen, S.B.S.), Norwegian University of Science and Technology, Trondheim, Norway; Unit for Hereditary Dementias (H.-H.C., C.G., B.K., L.Ö.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Medical Faculty (D.F., M.G.K.), University of Ljubljana, Slovenia; Fondazione IRCCS Ca'Granda (D.G., Elio Scarpini, M.S.), Ospedale Policlinico, Milan, Italy; Penn Center for Frontotemporal Degeneration (Murray Grossman), Philadelphia, PA; Universidad de Oviedo (M.M.-G.), Asturias, Spain; IRCCS Fondazione Don Carlo Gnocchi (B.N., S.S.), Florence; Istituto di Medicina Genomica (V.N.), Università Cattolica del sacro Cuore, Rome, Italy; Amsterdam Neuroscience (Y.A.L.P.), the Netherlands; Department of Medicine and Surgery (A.A.P.), University of Salerno, Baronissi (SA), Italy; Faculty of Chemistry and Chemical Technology (B.R.), University of Ljubljana, Slovenia; Institud d'Investigacions Biomèdiques August Pi i Sunyer (R.S.-V.), Barcelona, Spain; Department of Biomedical Sciences (J.V.d.Z., C.V.B.), University of Antwerp, Belgium; and Department of Comparative Biomedical Sciences (P.A.L.), The Royal Veterinary College, London, UK.

Objective: We sought to characterize expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.

Methods: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.

Results: We found pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [ = 2.17 × 10; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [ = 1.1 × 10; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.

Conclusions: Our results indicate correlation between pathogenic expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.
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http://dx.doi.org/10.1212/WNL.0000000000010914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836664PMC
December 2020

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

Int J Geriatr Psychiatry 2021 02 16;36(2):324-333. Epub 2020 Sep 16.

Servicio de geriatria, Hospital Universitario Ramon y Cajal, Madrid, Spain.

Objectives: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI.

Methods: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI.

Results: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI.

Conclusions: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.
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http://dx.doi.org/10.1002/gps.5427DOI Listing
February 2021

Clinical Applicability of the Specific Risk Score of Dementia in Type 2 Diabetes in the Identification of Patients with Early Cognitive Impairment: Results of the MOPEAD Study in Spain.

J Clin Med 2020 Aug 24;9(9). Epub 2020 Aug 24.

Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona (VHIR-UAB), 08035 Barcelona, Spain.

Introduction: Although the Diabetes Specific Dementia Risk Score (DSDRS) was proposed for predicting risk of dementia at 10 years, its usefulness as a screening tool is unknown. For this purpose, the European consortium MOPEAD included the DSDRS within the specific strategy for screening of cognitive impairment in type 2 diabetes (T2D) patients attended in a third-level hospital.

Material And Methods: T2D patients > 65 years, without known cognitive impairment, attended in a third-level hospital, were evaluated. As per MOPEAD protocol, patients with MMSE ≤ 27 or DSDRS ≥ 7 were referred to the memory clinic for complete neuropsychological assessment.

Results: 112 T2D patients were recruited. A total of 82 fulfilled the criteria for referral to the memory unit (43 of them declined referral: 48.8% for associated comorbidities, 37.2% lack of interest, 13.95% lack of social support). At the Fundació ACE's Memory Clinic, 34 cases (87.2%) of mild cognitive impairment (MCI) and 3 cases (7.7%) of dementia were diagnosed. The predictive value of DSDRS ≥ 7 as a screening tool of cognitive impairment was AUROC = 0.739, 0.024, CI 95% (0.609-0.825).

Conclusions: We found a high prevalence of unknown cognitive impairment in TD2 patients who attended a third-level hospital. The DSDRS was found to be a useful screening tool. The presence of associated comorbidities was the main factor of declining referral.
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http://dx.doi.org/10.3390/jcm9092726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565958PMC
August 2020

Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study.

PLoS Med 2020 08 20;17(8):e1003289. Epub 2020 Aug 20.

Department of Biochemistry and Molecular Biology, Lariboisière Hospital, APHP, Paris, France.

Background: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.

Methods And Findings: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD.

Conclusions: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.
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http://dx.doi.org/10.1371/journal.pmed.1003289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446786PMC
August 2020

Teleconsultation in a coloproctology unit during the COVID-19 pandemic. Preliminary results.

Cir Esp (Engl Ed) 2021 May 8;99(5):361-367. Epub 2020 Jul 8.

Hospital Universitari Mútua Terrassa, Tarrasa, España.

Introduction: During the state of alarm established in Spain due to the COVID-19 pandemic, most of the face-to-face outpatient consultations were cancelled and a telephone consultation was established to follow up coloproctological patients. The objective of this study was to analyse the efficacy of telemedicine (by telephone) in monitoring patients in a coloproctology unit, in the context of the COVID-19 pandemic.

Method: Prospective descriptive study of consecutive patients in a single centre. The result of the teleconsultation was classified as discharge, resolved visit or reprogramming and was analysed by different diagnostic groups.

Results: From March 19th to April 17th, 2020, the teleconsultation of 190 patients was carried out. The response rate was 94.2% (179). The diagnostic categories of the patients attended were: 51 (26.9%) colorectal neoplasia, 48 (25.3%) proctological pathology, 72 (37.9%) pelvic floor dysfunctions and 19 (10%) other benign pathologies. 105 (55.26%) could be recited as if they had come in person. Eleven (5.8%) patients were discharged. No significant differences were found between the different diagnostic categories and the resolution of the teleconsultation. The reasons for reprogramming are analyzed in the study.

Conclusion: In the context of a pandemic, teleconsultation has allowed 61% of follow-up visits to be definitively solved, avoiding the reprogramming of 116 patients. The new social and health paradigm after the pandemic will require a rethinking of our healthcare model, and in many aspects, telemedicine can offer tools for this.
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http://dx.doi.org/10.1016/j.ciresp.2020.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075819PMC
May 2021

A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study.

Alzheimers Dement 2020 10 27;16(10):1412-1425. Epub 2020 Jul 27.

Alzheimer's Research Group, Grifols, Barcelona, Spain.

Introduction: This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild-to-moderate Alzheimer's disease (AD).

Methods: Three hundred forty-seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham).

Results: PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales.

Discussion: This trial suggests that PE with albumin replacement could slow cognitive and functional decline in AD, although further studies are warranted.
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http://dx.doi.org/10.1002/alz.12137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984263PMC
October 2020

The combined effect of amyloid-β and tau biomarkers on brain atrophy in dementia with Lewy bodies.

Neuroimage Clin 2020 2;27:102333. Epub 2020 Jul 2.

Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Alzheimer's disease (AD)-related pathology is frequently found in patients with dementia with Lewy bodies (DLB). However, it is unknown how amyloid-β and tau-related pathologies influence neurodegeneration in DLB. Understanding the mechanisms underlying brain atrophy in DLB can improve our knowledge about disease progression, differential diagnosis, drug development and testing of anti-amyloid and anti-tau therapies in DLB.

Objectives: We aimed at investigating the combined effect of CSF amyloid-β42, phosphorylated tau and total tau on regional brain atrophy in DLB in the European DLB (E-DLB) cohort.

Methods: 86 probable DLB patients from the E-DLB cohort with CSF and MRI data were included. Random forest was used to analyze the association of CSF biomarkers (predictors) with visual rating scales for medial temporal lobe atrophy (MTA), posterior atrophy (PA) and global cortical atrophy scale-frontal subscale (GCA-F) (outcomes), including age, sex, education and disease duration as extra predictors.

Results: DLB patients with abnormal MTA scores had abnormal CSF Aβ42, shorter disease duration and older age. DLB patients with abnormal PA scores had abnormal levels of CSF Aβ42 and p-tau, older age, lower education and shorter disease duration. Abnormal GCA-F scores were associated with lower education, male sex, and older age, but not with any AD-related CSF biomarker.

Conclusions: This study shows preliminary data on the potential combined effect of amyloid-β and tau-related pathologies on the integrity of posterior brain cortices in DLB patients, whereas only amyloid-β seems to be related to MTA. Future availability of α-synuclein biomarkers will help us to understand the effect of α-synuclein and AD-related pathologies on brain integrity in DLB.
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http://dx.doi.org/10.1016/j.nicl.2020.102333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363702PMC
July 2020

Dementia Care in Times of COVID-19: Experience at Fundació ACE in Barcelona, Spain.

J Alzheimers Dis 2020 ;76(1):33-40

Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.

Background: Fundació ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution.

Objective: To share our experience in adapting our model of care to the new situation to ensure continuity of care.

Methods: We detail the sequence of events and the actions taken within Fundació ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed.

Results: The total number of individuals being actively followed by Fundació ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began.

Discussion: We have shown that Fundació ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care.
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http://dx.doi.org/10.3233/JAD-200547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369075PMC
July 2020

Association between retinal thickness and β-amyloid brain accumulation in individuals with subjective cognitive decline: Fundació ACE Healthy Brain Initiative.

Alzheimers Res Ther 2020 03 31;12(1):37. Epub 2020 Mar 31.

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.

Background: Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer's disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive decline (SCD) has been proposed as a risk factor for progression to AD. There is little data about retinal changes in preclinical AD and their correlation with amyloid-β (Aβ) uptake.

Aims: We investigated the association of retinal thickness quantified by OCT with Aβ accumulation and conversion to mild cognitive impairment (MCI) over 24 months in individuals with SCD.

Methods: One hundred twenty-nine individuals with SCD enrolled in Fundació ACE Healthy Brain Initiative underwent comprehensive neuropsychological testing, OCT scan of the retina and florbetaben (FBB) positron emission tomography (PET) at baseline (v0) and after 24 months (v2). We assessed the association of sixteen retinal thickness measurements at baseline with FBB-PET status (+/-) and global standardize uptake value ratio (SUVR) as a continuous measure at v0 and v2 and their predictive value on clinical status change (conversion to mild cognitive impairment (MCI)) at v2.

Results: Mean age of the sample was 64.72 ± 7.27 years; 62.8% were females. Fifteen participants were classified as FBB-PET+ at baseline and 22 at v2. Every 1 μm of increased thickness in the inner nasal macular region conferred 8% and 6% higher probability of presenting a FBB-PET+ status at v0 (OR = 1.08, 95% CI = 1.02-1.14, p = 0.007) and v2 (OR = 1.06, 95% CI = 1.02-1.11, p = 0.004), respectively. Inner nasal macular thickness also positively correlated with global SUVR (at v0: β = 0.23, p = 0.004; at v2: β = 0.26, p = 0.001). No retinal measurements were associated to conversion to MCI over 24 months.

Conclusions: Subtle retinal thickness changes in the macular region are already present in SCD and correlate with Aβ uptake.
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http://dx.doi.org/10.1186/s13195-020-00602-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110730PMC
March 2020

A computerized version of the Short Form of the Face-Name Associative Memory Exam (FACEmemory®) for the early detection of Alzheimer's disease.

Alzheimers Res Ther 2020 03 16;12(1):25. Epub 2020 Mar 16.

Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Gran Via de Carles III, 85 bis, 08028, Barcelona, Spain.

Background: Computerized neuropsychological tests for early detection of Alzheimer's disease (AD) have attracted increasing interest. Memory for faces and proper names is a complex task because its association is arbitrary. It implicates associative occipito-temporal cerebral regions, which are disrupted in AD. The short form of the Face-Name Associative Memory Exam (FNAME-12), developed to detect preclinical and prodromal AD, asks individuals to learn the names and occupations associated with 12 faces. The current work advances this field by using voice recognition and touchscreen response format. The purpose of this study is to create the first self-administered episodic memory test, FACEmemory®, by adapting the FNAME-12 for tablet use with voice recognition, touchscreen answers, and automatic scoring. The test was minimally supervised by a psychologist to avoid technological problems during execution and scored manually to assess the reliability of the automatic scoring. The aims of the present study were (1) to determine whether FACEmemory® is a sensitive tool for the detection of cognitive impairment, (2) to examine whether performances on FACEmemory® are correlated with those on the S-FNAME (paper-and-pencil version with 16 images), and (3) to determine whether performances on FACEmemory® are related to AD biomarkers in the cerebrospinal fluid (CSF) (Aβ42, p-tau, and Aβ42/p-tau ratio).

Methods: FACEmemory® was completed by 154 cognitively healthy (CH) individuals and 122 subjects with mild cognitive impairment, of whom 61 were non-amnestic (naMCI) and 61 amnestic (aMCI). A subsample of 65 individuals completed the S-FNAME, and 65 subjects received lumbar punctures.

Results: Performance on FACEmemory® was progressively worse from CH to the naMCI and aMCI groups. A cutoff of 31.5 in total FACEmemory® obtained 80.5% and 80.3% sensitivity and specificity values, respectively, for discriminating between CH and aMCI. Automatically corrected FACEmemory® scores were highly correlated with the manually corrected ones. FACEmemory® scores and AD CSF biomarker levels were significantly correlated as well, mainly in the aMCI group.

Conclusions: FACEmemory® may be a promising memory prescreening tool for detecting subtle memory deficits related to AD. Our findings suggest FACEmemory® performance provides a useful gradation of impairment from normal aging to aMCI, and it is related to CSF AD biomarkers.
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http://dx.doi.org/10.1186/s13195-020-00594-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077028PMC
March 2020