Carla Abdelnour

All Publications

• The Parkinson's Disease Composite of Executive Functioning: A Measure for Detecting Cognitive Decline in Clinical Trials. Neurology Young, C. B., Cholerton, B., Smith, A. M., Shahid-Besanti, M., Abdelnour, C., Mormino, E. C., Hu, S. C., Chung, K. A., Peterson, A., Rosenthal, L., Pantelyat, A., Dawson, T. M., Quinn, J., Zabetian, C. P., Montine, T. J., Poston, K. L. 2024; 103 (2): e209609

  Abstract

  Executive functioning is one of the first domains to be impaired in Parkinson disease (PD), and the majority of patients with PD eventually develop dementia. Thus, developing a cognitive endpoint measure specifically assessing executive functioning is critical for PD clinical trials. The objective of this study was to develop a cognitive composite measure that is sensitive to decline in executive functioning for use in PD clinical trials.We used cross-sectional and longitudinal follow-up data from PD participants enrolled in the PD Cognitive Genetics Consortium, a multicenter setting focused on PD. All PD participants with Trail Making Test, Digit Symbol, Letter-Number Sequencing, Semantic Fluency, and Phonemic Fluency neuropsychological data collected from March 2010 to February 2020 were included. Baseline executive functioning data were used to create the Parkinson's Disease Composite of Executive Functioning (PaCEF) through confirmatory factor analysis. We examined the changes in the PaCEF over time, how well baseline PaCEF predicts time to cognitive progression, and the required sample size estimates for PD clinical trials. PaCEF results were compared with the Montreal Cognitive Assessment (MoCA), individual tests forming the PaCEF, and tests of visuospatial, language, and memory functioning.A total of 841 participants (251 no cognitive impairment [NCI], 480 mild cognitive impairment [MCI], and 110 dementia) with baseline data were included, of which the mean (SD) age was 67.1 (8.9) years and 270 were women (32%). Five hundred forty five PD participants had longitudinal neuropsychological data spanning 9 years (mean [SD] 4.5 [2.2] years) and were included in analyses examining cognitive decline. A 1-factor model of executive functioning with excellent fit (comparative fit index = 0.993, Tucker-Lewis index = 0.989, and root mean square error of approximation = 0.044) was used to calculate the PaCEF. The average annual change in PaCEF ranged from 0.246 points per year for PD-NCI participants who remained cognitively unimpaired to -0.821 points per year for PD-MCI participants who progressed to dementia. For PD-MCI, baseline PaCEF, but not baseline MoCA, significantly predicted time to dementia. Sample size estimates were 69%-73% smaller for PD-NCI trials and 16%-19% smaller for PD-MCI trials when using the PaCEF rather than MoCA as the endpoint.The PaCEF is a sensitive measure of executive functioning decline in PD and will be especially beneficial for PD clinical trials.

  View details for DOI 10.1212/WNL.0000000000209609

  View details for PubMedID 38870440

• Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease. Annals of neurology Abdelnour, C., Young, C. B., Shahid-Besanti, M., Smith, A., Wilson, E. N., Ramos Benitez, J., Vossler, H., Plastini, M. J., Winer, J. R., Kerchner, G. A., Cholerton, B., Andreasson, K. I., Henderson, V. W., Yutsis, M., Montine, T. J., Tian, L., Mormino, E. C., Poston, K. L. 2024

  Abstract

  To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD).We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid-β PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes.Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment.Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024.

  View details for DOI 10.1002/ana.27003

  View details for PubMedID 38888142

• Decentralized clinical trials for medications to reduce the risk of dementia: Consensus report and guidance. Alzheimer's & dementia : the journal of the Alzheimer's Association Howard, L., Abdelnour, C., Abner, E. L., Allegri, R. F., Dodge, H. H., Gauthier, S., Hoyos, C. M., Jicha, G. A., Kehoe, P. G., Mummery, C. J., Ogunniyi, A., Scarmeas, N., Chen, X., Titiner, J. R., Weber, C. R., Peters, R. 2024

  Abstract

  Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field.A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations.Overall, the recommendations support the delivery of decentralized trials in dementia prevention provided adequate safety checks and balances are included. A total of 40 recommendations are presented, spanning aspects of decentralized clinical trials, including safety, dispensing, outcome assessment, and data collection.These recommendations provide an accessible, pragmatic guide for the design and conduct of remote medication trials for dementia prevention.Clinical trials of medication have begun adopting decentralized approaches. Researchers in the field lack guidance on what would be appropriate circumstances and frameworks for what would be appropriate circumstances and frameworks for the use of decentralized trial methods in dementia prevention. The present report provides consensus-based expert recommendations for decentralized clinical trials for dementia prevention.

  View details for DOI 10.1002/alz.13891

  View details for PubMedID 38824659

• Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer's Disease: A Pragmatic Review for Clinicians. Neurology and therapy Wyman-Chick, K. A., Chaudhury, P., Bayram, E., Abdelnour, C., Matar, E., Chiu, S. Y., Ferreira, D., Hamilton, C. A., Donaghy, P. C., Rodriguez-Porcel, F., Toledo, J. B., Habich, A., Barrett, M. J., Patel, B., Jaramillo-Jimenez, A., Scott, G. D., Kane, J. P. 2024

  Abstract

  This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

  View details for DOI 10.1007/s40120-024-00620-x

  View details for PubMedID 38720013

  View details for PubMedCentralID 5815202

• Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra. Annals of clinical and translational neurology Plastini, M. J., Abdelnour, C., Young, C. B., Wilson, E. N., Shahid-Besanti, M., Lamoureux, J., Andreasson, K. I., Kerchner, G. A., Montine, T. J., Henderson, V. W., Poston, K. L. 2024

  Abstract

  More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD.Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra.Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2 (2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2 (2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2 (3) = 13.87, p = 0.003).Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

  View details for DOI 10.1002/acn3.52034

  View details for PubMedID 38436140

• Clinical trials in dementia with Lewy bodies: the evolving concept of co-pathologies, patient selection and biomarkers. Current opinion in neurology Gibson, L. L., Abdelnour, C., Chong, J., Ballard, C., Aarsland, D. 2023

  Abstract

  PURPOSE OF REVIEW: Currently, no disease modifying therapies (DMTs) have been approved for use in dementia with Lewy bodies (DLB). Clinical trials face difficulties due to the clinical and neuropathological heterogeneity of the condition with a diverse array of neuropathogenic mechanisms contributing to the clinical phenotype. The purpose of this review is to describe how recent advances in the development of biofluid biomarkers may be used in clinical trials to tackle some of these challenges.RECENT FINDINGS: Biomarkers are essential both to support the accurate diagnosis of DLB and to delineate the influence of coexisting pathologies. Recent advances in the development of alpha-synuclein seeding amplification assays (SAA) allow accurate identification of alpha-synuclein from the prodromal stages in DLB. Additionally, validation of plasma phosphorylated tau assays in DLB is ongoing and offers an accessible biomarker to indicate the existence of AD co-pathology. Use of biomarkers for diagnosis and group stratification in clinical trials of DLB is growing and likely to be of increasing importance in the future.SUMMARY: In vivo biomarkers can enhance patient selection in clinical trials allowing greater diagnostic accuracy, a more homogeneous trial population, and stratification by co-pathology to create subgroups most likely to derive therapeutic benefit from DMTs.

  View details for DOI 10.1097/WCO.0000000000001173

  View details for PubMedID 37387459

• Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia. Movement disorders clinical practice Gonzalez, M. C., Tovar-Rios, D. A., Alves, G., Dalen, I., Williams-Gray, C. H., Camacho, M., Forsgren, L., Bäckström, D., Lawson, R. A., Macleod, A. D., Counsell, C. E., Paquet, C., DeLena, C., D'Antonio, F., Pilotto, A., Padovani, A., Blanc, F., Falup-Pecurariu, C., Lewis, S. J., Rejdak, K., Papuc, E., Hort, J., Nedelska, Z., O'Brien, J., Bonanni, L., Marquié, M., Boada, M., Pytel, V., Abdelnour, C., Alcolea, D., Beyer, K., Tysnes, O. B., Aarsland, D., Maple-Grødem, J. 2023; 10 (6): 980-986

  Abstract

  There is a need to better understand the rate of cognitive and motor decline of Dementia with Lewy bodies (DLB) and Parkinson's disease Dementia (PDD).To compare the rate of cognitive and motor decline in patients with DLB and PDD from the E-DLB Consortium and the Parkinson's Incidence Cohorts Collaboration (PICC) Cohorts.The annual change in MMSE and MDS-UPDRS part III was estimated using linear mixed regression models in patients with at least one follow-up (DLB n = 837 and PDD n = 157).When adjusting for confounders, we found no difference in the annual change in MMSE between DLB and PDD (-1.8 [95% CI -2.3, -1.3] vs. -1.9 [95% CI -2.6, -1.2] [P = 0.74]). MDS-UPDRS part III showed nearly identical annual changes (DLB 4.8 [95% CI 2.1, 7.5]) (PDD 4.8 [95% CI 2.7, 6.9], [P = 0.98]).DLB and PDD showed similar rates of cognitive and motor decline. This is relevant for future clinical trial designs.

  View details for DOI 10.1002/mdc3.13752

  View details for PubMedID 37332651

  View details for PubMedCentralID PMC10272890

• Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022. Neurology and therapy Abdelnour, C., Gonzalez, M. C., Gibson, L. L., Poston, K. L., Ballard, C. G., Cummings, J. L., Aarsland, D. 2023

  Abstract

  Reviews of randomized clinical trials (RCTs) in dementia with Lewy bodies (DLB) are essential for informing ongoing research efforts of symptomatic therapies and potentially disease-modifying therapies (DMTs).We performed a systematic review of all clinical trials conducted until September 27, 2022, by examining 3 international registries: ClinicalTrials.gov, the European Union Drug Regulating Authorities Clinical Trials Database, and the International Clinical Trials Registry Platform, to identify drugs in trials in DLB.We found 25 agents in 40 trials assessing symptomatic treatments and DMTs for DLB: 7 phase 3, 31 phase 2, and 2 phase 1 trials. We found an active pipeline for drug development in DLB, with most ongoing clinical trials in phase 2. We identified a recent trend towards including participants at the prodromal stages, although more than half of active clinical trials will enroll mild to moderate dementia patients. Additionally, repurposed agents are frequently tested, representing 65% of clinical trials.Current challenges in DLB clinical trials include the need for disease-specific outcome measures and biomarkers, and improving representation of global and diverse populations.

  View details for DOI 10.1007/s40120-023-00467-8

  View details for PubMedID 37017910

  View details for PubMedCentralID 6823159

• A randomized, open-label clinical trial in mild cognitive impairment with EGb 761 examining blood markers of inflammation and oxidative stress. Scientific reports Morato, X., Marquie, M., Tartari, J. P., Lafuente, A., Abdelnour, C., Alegret, M., Jofresa, S., Buendia, M., Pancho, A., Aguilera, N., Ibarria, M., Diego, S., Cuevas, R., Canada, L., Calvet, A., Antonio, E. E., Perez-Cordon, A., Sanabria, A., de Rojas, I., Nunez-Llaves, R., Cano, A., Orellana, A., Montrreal, L., Canabate, P., Rosende-Roca, M., Vargas, L., Bojaryn, U., Ricciardi, M., Ariton, D. M., Espinosa, A., Ortega, G., Munoz, N., Lleonart, N., Alarcon-Martin, E., Moreno, M., Preckler, S., Tantinya, N., Ramis, M., Nogales, A. B., Seguer, S., Martin, E., Pytel, V., Valero, S., Gurruchaga, M., Tarraga, L., Ruiz, A., Boada, M. 2023; 13 (1): 5406

  Abstract

  Although beta-amyloid (Abeta) and phosphorylated tau remain the preferred targets for disease-modifying treatments (DMT) against Alzheimer's disease (AD), part of the pathophysiological mechanisms of cognitive impairment are related to neuroinflammation and oxidative stress. In mild cognitive impairment (MCI), a prodromal stage of AD and other neurodegenerative conditions, the joint appearance of inflammation, oxidative stress, and metabolic alterations are the common pathways of neurotoxicity and neurodegeneration. The standardized extract of Ginkgo biloba EGb 761 interferes with the pathogenic mechanisms involved in both the development of cognitive impairment due to AD and that of vascular origin. The primary objective of this study is to compare changes in the levels of blood markers of inflammation and oxidative stress after treatment with EGb 761 in a cohort of 100 patients with MCI. In addition, we aim to assess changes in these blood markers during an additional 12-month extension phase in which patients in the control group will also receive EGb 761 and patients in the active group will extend their treatment duration. Secondary objectives include comparing changes in neuropsychiatric and cognitive test scores between the baseline (v0) and 12-month visits (v2). This study is a Phase IV, single-center, randomized, open-label, parallel-group clinical trial consisting of the 12-month follow-up of a cohort of participants with MCI [Global Deterioration Scale (GDS)=3] and an extension with an additional 12-month follow-up. During the first 12months, participants will be randomized into two arms: in one arm, patients will receive 1 daily tablet of EGb 761 240mg orally (study group, n=50), while in the other arm, patients will not receive EGb 761 and will undergo the same assessments as the treated group (control group, n=50). After the first 12months of the study, patients in the EGb 761-treated group will continue treatment, and patients in the control group will be offered one EGb 761 240mg tablet per day orally. All participants will be monitored for an additional 12months. A battery of blood markers of inflammation and oxidative stress will be quantified at v0, v1, v2, v3, and v4. The Olink Proteomics panel of inflammation markers ( https://www.olink.com/products/inflammation/ ) will be used to evaluate 92 proteins associated with inflammatory diseases and related biological processes. The second panel measures 92 proteins involved in neurological processes. At v0, v2, and v4, neuropsychological and neurological evaluations will be conducted in addition to vital signs and anthropometric studies using a body composition monitor with bioimpedance technology (Tanita). Sixty percent of the 100 MCI patients recruited were women. The mean age was 73.1years, and the mean time between symptom onset and MCI diagnosis was 2.9years. The mean Mini-Mental State Examination (MMSE) score was 26.7. Depressive and anxiety disorders, as well as vascular risk factors, were the most frequent comorbidities among the cohort. The study is still ongoing, and results for the first year of treatment (v0, v1, v2) are expected by 2023. Individuals with MCI have an elevated risk of developing dementia. EGb 761 is used worldwide for the symptomatic treatment of cognitive disorders due to its neuroprotective effects. In experimental models and clinical observational studies, EGb 761 has shown strong antioxidant and anti-inflammatory activity. As a result, this study has been proposed to evaluate the antioxidant and anti-inflammatory effects on plasma markers and their potential clinical correlation with the progression of cognitive decline in patients with MCI.Trial registration: Registro Espanol de estudios clinicos (REec) number 2020-003776-41, ClinicalTrials.gov Identifier: NCT05594355.

  View details for DOI 10.1038/s41598-023-32515-6

  View details for PubMedID 37012306

• Cognitive Impairment in Neurodegenerative Movement Disorders. Seminars in neurology Abdelnour, C., Poston, K. L. 2023

  Abstract

  Patients with neurodegenerative movement disorders can develop cognitive impairment during the disease. Cognitive symptoms have been associated with decreased quality of life, higher caregiver burden, and earlier institutionalization, and are therefore critical for physicians to understand and address. The evaluation of cognitive performance of patients with neurodegenerative movement disorders is important for providing adequate diagnosis, management, prognosis, and support patients and their caregivers. In this review, we discuss the features of the cognitive impairment profile of commonly encountered movement disorders: Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, and Huntington's disease. In addition, we provide neurologists with practical guidance and evaluation tools for the assessment and management of these challenging patients.

  View details for DOI 10.1055/s-0043-1764204

  View details for PubMedID 36940727

• Ethical challenges of using remote monitoring technologies for clinical research: A case study of the role of local research ethics committees in the RADAR-AD study. PloS one Muurling, M., Pasmooij, A. M., Koychev, I., Roik, D., Froelich, L., Schwertner, E., Religa, D., Abdelnour, C., Boada, M., Almici, M., Galluzzi, S., Cardoso, S., de Mendonca, A., Owens, A. P., Kuruppu, S., Gjestsen, M. T., Lazarou, I., Gkioka, M., Tsolaki, M., Diaz, A., Gove, D., Visser, P. J., Aarsland, D., Lucivero, F., de Boer, C., RADAR-AD Consortium 2023; 18 (7): e0285807

  Abstract

  INTRODUCTION: Clinical research with remote monitoring technologies (RMTs) has multiple advantages over standard paper-pencil tests, but also raises several ethical concerns. While several studies have addressed the issue of governance of big data in clinical research from the legal or ethical perspectives, the viewpoint of local research ethics committee (REC) members is underrepresented in the current literature. The aim of this study is therefore to find which specific ethical challenges are raised by RECs in the context of a large European study on remote monitoring in all syndromic stages of Alzheimer's disease, and what gaps remain.METHODS: Documents describing the REC review process at 10 sites in 9 European countries from the project Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR-AD) were collected and translated. Main themes emerging in the documents were identified using a qualitative analysis approach.RESULTS: Four main themes emerged after analysis: data management, participant's wellbeing, methodological issues, and the issue of defining the regulatory category of RMTs. Review processes differed across sites: process duration varied from 71 to 423 days, some RECs did not raise any issues, whereas others raised up to 35 concerns, and the approval of a data protection officer was needed in half of the sites.DISCUSSION: The differences in the ethics review process of the same study protocol across different local settings suggest that a multi-site study would benefit from a harmonization in research ethics governance processes. More specifically, some best practices could be included in ethical reviews across institutional and national contexts, such as the opinion of an institutional data protection officer, patient advisory board reviews of the protocol and plans for how ethical reflection is embedded within the study.

  View details for DOI 10.1371/journal.pone.0285807

  View details for PubMedID 37418385

• Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design ALZHEIMERS & DEMENTIA Toledo, J. B., Abdelnour, C., Weil, R. S., Ferreira, D., Rodriguez-Porcel, F., Pilotto, A., Wyman-Chick, K. A., Grothe, M. J., Kane, J. M., Taylor, A., Rongve, A., Scholz, S., Leverenz, J. B., Boeve, B. F., Aarsland, D., McKeith, I. G., Lewis, S., Leroi, I., Taylor, J. P., ISTAART Lewy Body Dementias Trial 2023; 19 (1): 318-332

  Abstract

  Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.

  View details for DOI 10.1002/alz.12814

  View details for Web of Science ID 000867854100001

  View details for PubMedID 36239924

  View details for PubMedCentralID PMC9881193

• Perspectives and challenges in patient stratification in Alzheimer's disease ALZHEIMERS RESEARCH & THERAPY Abdelnour, C., Agosta, F., Bozzali, M., Fougere, B., Iwata, A., Nilforooshan, R., Takada, L. T., Vinuela, F., Traber, M. 2022; 14 (1): 112

  Abstract

  Patient stratification is the division of a patient population into distinct subgroups based on the presence or absence of particular disease characteristics. As patient stratification can be used to account for the underlying pathology of a disease, it can help physicians to tailor therapeutic interventions to individuals and optimize their care management and treatment regime. Alzheimer's disease, the most common form of dementia, is a heterogeneous disease and its management benefits from patient stratification in clinical trials, and the development of personalized care and treatment strategies for people living with the disease.In this review, we discuss the importance of the stratification of people living with Alzheimer's disease, the challenges associated with early diagnosis and patient stratification, and the evolution of patient stratification once disease-modifying therapies become widely available.Patient stratification plays an important role in drug development in clinical trials and may play an even larger role in clinical practice. A timely diagnosis and stratification of people living with Alzheimer's disease is paramount in determining people who are at risk of progressing from mild cognitive impairment to Alzheimer's dementia. There are key issues associated with stratifying patients which include the heterogeneity and complex neurobiology behind Alzheimer's disease, our inadequately prepared healthcare systems, and the cultural perceptions of Alzheimer's disease. Stratifying people living with Alzheimer's disease may be the key in establishing precision and personalized medicine in the field, optimizing disease prevention and pharmaceutical treatment to slow or stop cognitive decline, while minimizing adverse effects.

  View details for DOI 10.1186/s13195-022-01055-y

  View details for Web of Science ID 000840313700001

  View details for PubMedID 35964143

  View details for PubMedCentralID PMC9375274

• Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations TRANSLATIONAL NEURODEGENERATION Rodriguez-Porcel, F., Wyman-Chick, K. A., Abdelnour Ruiz, C., Toledo, J. B., Ferreira, D., Urwyler, P., Weil, R. S., Kane, J., Pilotto, A., Rongve, A., Boeve, B., Taylor, J., McKeith, I., Aarsland, D., Lewis, S. G., Lewy Body Dementias Professional I 2022; 11 (1): 24

  Abstract

  The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.

  View details for DOI 10.1186/s40035-022-00299-w

  View details for Web of Science ID 000789149200001

  View details for PubMedID 35491418

  View details for PubMedCentralID PMC9059356

• Evaluation of the Feasibility, Safety and Efficacy of the Use of Intravenous Infusions of Adenosine Triphosphate (ATP) in People Affected by Moderate to Severe Alzheimer's Disease: A Double-Blind Masked Clinical Trial for Dose Finding JPAD-JOURNAL OF PREVENTION OF ALZHEIMERS DISEASE Ruiz, A., Sanchez, D., Lafuente, A., Ortega, G., Buendia, M., Papasey, J., Jimeno, S. Y., Badia, F. P., Palacio, M. E., Abdelnour, C., Ramirez-Torano, F., Maestu, F., Saez, M. E., Tarraga, L., Dagnelie, P. C., Boada, M. 2022; 9 (3): 425-434

  Abstract

  There are currently no drug therapies modifying the natural history of patients suffering Alzheimer's disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented.To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion.A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates.A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions.The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables.Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.

  View details for DOI 10.14283/jpad.2022.38

  View details for Web of Science ID 000784600700001

  View details for PubMedID 35841243

• Introducing CARESSER: A framework for in situ learning robot social assistance from expert knowledge and demonstrations USER MODELING AND USER-ADAPTED INTERACTION Andriella, A., Torras, C., Abdelnour, C., Alenya, G. 2022: 1-56

  Abstract

  Socially assistive robots have the potential to augment and enhance therapist's effectiveness in repetitive tasks such as cognitive therapies. However, their contribution has generally been limited as domain experts have not been fully involved in the entire pipeline of the design process as well as in the automatisation of the robots' behaviour. In this article, we present aCtive leARning agEnt aSsiStive bEhaviouR (CARESSER), a novel framework that actively learns robotic assistive behaviour by leveraging the therapist's expertise (knowledge-driven approach) and their demonstrations (data-driven approach). By exploiting that hybrid approach, the presented method enables in situ fast learning, in a fully autonomous fashion, of personalised patient-specific policies. With the purpose of evaluating our framework, we conducted two user studies in a daily care centre in which older adults affected by mild dementia and mild cognitive impairment (N = 22) were requested to solve cognitive exercises with the support of a therapist and later on of a robot endowed with CARESSER. Results showed that: (i) the robot managed to keep the patients' performance stable during the sessions even more so than the therapist; (ii) the assistance offered by the robot during the sessions eventually matched the therapist's preferences. We conclude that CARESSER, with its stakeholder-centric design, can pave the way to new AI approaches that learn by leveraging human-human interactions along with human expertise, which has the benefits of speeding up the learning process, eliminating the need for the design of complex reward functions, and finally avoiding undesired states.

  View details for DOI 10.1007/s11257-021-09316-5

  View details for Web of Science ID 000767689800001

  View details for PubMedID 35311217

  View details for PubMedCentralID PMC8916953

• Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type BRAIN Adami, P., Orellana, A., Garcia, P., Kleineidam, L., Alarcon-Martin, E., Montrreal, L., Aguilera, N., Espinosa, A., Abdelnour, C., Rosende-Roca, M., Pablo Tartari, J., Vargas, L., Mauleon, A., Esteban-De Antonio, E., Lopez-Cuevas, R., Dalmasso, M., Martin, R., Parveen, K., Fuentes, V., Amin, N., Ahmad, S., Ikram, M., Lewczuk, P., Kornhuber, J., Peters, O., Froelich, L., Ruether, E., Wiltfang, J., Tarraga, L., Boada, M., Maier, W., de Rojas, I., Cano, A., Sanabria, A., Alegret, M., Hernandez, I., Marquie, M., Valero, S., van Duijn, C. M., Wagner, M., Jessen, F., Schneider, A., Saez Goni, M., Gonzalez Perez, A., Ruiz, A., Ramirez, A. 2022; 145 (7): 2507-2517

  Abstract

  Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-β 42 (Aβ42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aβ42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aβ42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aβ42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.

  View details for DOI 10.1093/brain/awac024

  View details for Web of Science ID 000805815200001

  View details for PubMedID 35088840

• Parsing heterogeneity within dementia with Lewy bodies using clustering of biological, clinical, and demographic data ALZHEIMERS RESEARCH & THERAPY Abdelnour, C., Ferreira, D., van de Beek, M., Cedres, N., Oppedal, K., Cavallin, L., Blanc, F., Bousiges, O., Wahlund, L., Pilotto, A., Padovani, A., Boada, M., Pagonabarraga, J., Kulisevsky, J., Aarsland, D., Lemstra, A. W., Westman, E. 2022; 14 (1): 14

  Abstract

  Dementia with Lewy bodies (DLB) includes various core clinical features that result in different phenotypes. In addition, Alzheimer's disease (AD) and cerebrovascular pathologies are common in DLB. All this increases the heterogeneity within DLB and hampers clinical diagnosis. We addressed this heterogeneity by investigating subgroups of patients with similar biological, clinical, and demographic features.We studied 107 extensively phenotyped DLB patients from the European DLB consortium. Factorial analysis of mixed data (FAMD) was used to identify dimensions in the data, based on sex, age, years of education, disease duration, Mini-Mental State Examination (MMSE), cerebrospinal fluid (CSF) levels of AD biomarkers, core features of DLB, and regional brain atrophy. Subsequently, hierarchical clustering analysis was used to subgroup individuals based on the FAMD dimensions.We identified 3 dimensions using FAMD that explained 38% of the variance. Subsequent hierarchical clustering identified 4 clusters. Cluster 1 was characterized by amyloid-β and cerebrovascular pathologies, medial temporal atrophy, and cognitive fluctuations. Cluster 2 had posterior atrophy and showed the lowest frequency of visual hallucinations and cognitive fluctuations and the worst cognitive performance. Cluster 3 had the highest frequency of tau pathology, showed posterior atrophy, and had a low frequency of parkinsonism. Cluster 4 had virtually normal AD biomarkers, the least regional brain atrophy and cerebrovascular pathology, and the highest MMSE scores.This study demonstrates that there are subgroups of DLB patients with different biological, clinical, and demographic characteristics. These findings may have implications in the diagnosis and prognosis of DLB, as well as in the treatment response in clinical trials.

  View details for DOI 10.1186/s13195-021-00946-w

  View details for Web of Science ID 000745517500002

  View details for PubMedID 35063023

  View details for PubMedCentralID PMC8783432

• Alzheimer's disease diagnosis and management: Perspectives from around the world ALZHEIMER'S & DEMENTIA: DIAGNOSIS, ASSESSMENT & DISEASE MONITORING Kerwin, D., Abdelnour, C., Caramelli, P., Ogunniyi, A., Shi, J., Zetterberg, H., Traber, M. 2022; 14 (1): e12334

  Abstract

  Alzheimer's disease (AD) and other dementias are a global challenge. Early diagnosis is important to manage the disease. However, there are barriers to diagnosis that differ by region. Researchers from Brazil, China, Nigeria, Spain, and Sweden have identified key barriers to AD diagnosis in their countries. In Brazil, socioeconomic inequalities and poor recognition of dementia by physicians can prevent diagnosis. In China, a very large population and lack of physician training in dementia make diagnosis problematic. In Nigeria, socioeconomic inequalities and cultural stigma can stand in the way of diagnosis. In Spain, patient hesitancy and an overloaded health-care system are barriers to diagnosis. In Sweden, inconsistent use of biomarkers is a prominent barrier to diagnosis of AD. To support diagnosis, more focus is needed on education of patients and physicians, increased use of support services, and improved access to biomarkers to accurately diagnose AD.

  View details for DOI 10.1002/dad2.12334

  View details for Web of Science ID 000914865700072

  View details for PubMedID 35898519

  View details for PubMedCentralID PMC9309007

• Association of Plasma p-tau181 and p-tau231 Concentrations With Cognitive Decline in Patients With Probable Dementia With Lewy Bodies JAMA NEUROLOGY Gonzalez, M. C., Ashton, N. J., Gomes, B., Tovar-Rios, D., Blanc, F., Karikari, T. K., Mollenhauer, B., Pilotto, A., Lemstra, A., Paquet, C., Abdelnour, C., Kramberger, M. G., Bonanni, L., Vandenberghe, R., Hye, A., Blennow, K., Zetterberg, H., Aarsland, D., European-Dementia Lewy Bodies E-DL 2022; 79 (1): 32-37

  Abstract

  Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-β and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder.To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB.This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205).The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition.Among this cohort of 987 patients (512 men [51.9%]; mean [SD] age, 70.0 [8.8] years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-β42 levels compared with those with normal levels (difference in the groups in p-tau181, -3.61 pg/mL; 95% CI, -5.43 to -1.79 pg/mL; P = .049; difference in the groups in p-tau231, -2.51 pg/mL; 95% CI, -3.63 to -1.39 pg/mL; P = .02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aβ42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, -0.092 MMSE points; 95% CI, -0.12 to -0.06 MMSE points; P = .001; for p-tau231, -0.16 MMSE points; 95% CI, -0.21 to -0.12 MMSE points; P < .001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of -0.094 MMSE points per year (95% CI, -0.144 to -0.052 MMSE points; P = .02), whereas plasma p-tau231 level was associated with an annual decrease of -0.130 MMSE points (95% CI, -0.201 to -0.071 MMSE points; P = .02), after adjusting for sex and age.This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB.

  View details for DOI 10.1001/jamaneurol.2021.4222

  View details for Web of Science ID 000722721200005

  View details for PubMedID 34807233

  View details for PubMedCentralID PMC8609462

• beta-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies NEUROLOGY Ferreira, D., Przybelski, S. A., Lesnick, T. G., Lemstra, A. W., Londos, E., Blanc, F., Nedelska, Z., Schwarz, C. G., Graff-Radford, J., Senjem, M. L., Fields, J. A., Knopman, D. S., Savica, R., Ferman, T. J., Graff-Radford, N. R., Lowe, V. J., Jack, C. R., Petersen, R. C., Mollenhauer, B., Garcia-Ptacek, S., Abdelnour, C., Hort, J., Bonanni, L., Oppedal, K., Kramberger, M. G., Boeve, B. F., Aarsland, D., Westman, E., Kantarci, K. 2020; 95 (24): E3257-E3268

  Abstract

  In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype.We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid1-42 and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+.A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in APOE ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.

  View details for DOI 10.1212/WNL.0000000000010943

  View details for Web of Science ID 000607315800022

  View details for PubMedID 32989106

  View details for PubMedCentralID PMC7836666

• CSF tau proteins correlate with an atypical clinical presentation in dementia with Lewy bodies JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Di Censo, R., Abdelnour, C., Blanc, F., Bousiges, O., Lemstra, A. W., van Steenoven, I., Onofrj, M., Aarsland, D., Bonanni, L., European DLB Consortium 2020; 91 (1): 109-110

  View details for DOI 10.1136/jnnp-2019-320980

  View details for Web of Science ID 000507335200021

  View details for PubMedID 31366604

• The combined effect of amyloid-beta and tau biomarkers on brain atrophy in dementia with Lewy bodies NEUROIMAGE-CLINICAL Abdelnour, C., Ferreira, D., Oppedal, K., Cavallin, L., Bousiges, O., Wahlund, L., Hort, J., Nedelska, Z., Padovani, A., Pilotto, A., Bonanni, L., Kramberger, M. G., Boada, M., Westman, E., Pagonabarraga, J., Kulisevsky, J., Blanc, F., Aarsland, D. 2020; 27: 102333

  Abstract

  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.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.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.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.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.

  View details for DOI 10.1016/j.nicl.2020.102333

  View details for Web of Science ID 000562965000011

  View details for PubMedID 32674011

  View details for PubMedCentralID PMC7363702

• GBA and APOE epsilon 4 associate with sporadic dementia with Lewy bodies in European genome wide association study SCIENTIFIC REPORTS Rongve, A., Witoelar, A., Ruiz, A., Athanasiu, L., Abdelnour, C., Clarimon, J., Heilmann-Heimbach, S., Hernandez, I., Moreno-Grau, S., de Rojas, I., Morenas-Rodriguez, E., Fladby, T., Sando, S. B., Brathen, G., Blanc, F., Bousiges, O., Lemstra, A. W., van Steenoven, I., Londos, E., Almdahl, I. S., Palhaugen, L., Eriksen, J. A., Djurovic, S., Stordal, E., Saltvedt, I., Ulstein, I. D., Bettella, F., Desikan, R. S., Idland, A., Toft, M., Pihlstrom, L., Snaedal, J., Tarraga, L., Boada, M., Lleo, A., Stefansson, H., Stefansson, K., Ramirez, A., Aarsland, D., Andreassen, O. A. 2019; 9: 7013

  Abstract

  Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10-8). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10-6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

  View details for DOI 10.1038/s41598-019-43458-2

  View details for Web of Science ID 000467137300012

  View details for PubMedID 31065058

  View details for PubMedCentralID PMC6504850

• The Spanish version of Face-Name Associative Memory Exam (S-FNAME) performance is related to amyloid burden in Subjective Cognitive Decline SCIENTIFIC REPORTS Sanabria, A., Alegret, M., Rodriguez-Gomez, O., Valero, S., Sotolongo-Grau, O., Monte-Rubio, G., Abdelnour, C., Espinosa, A., Ortega, G., Perez-Cordon, A., Gailhajanet, A., Hernandez, I., Rosende-Roca, M., Vargas, L., Mauleon, A., Sanchez, D., Martin, E., Rentz, D. M., Lomena, F., Ruiz, A., Tarraga, L., Boada, M., FACEHBI Study Grp 2018; 8: 3828

  Abstract

  The Face-Name Associative Memory Exam (FNAME) is a paired associative memory test created to detect memory deficits in individuals with preclinical Alzheimer's disease (AD). Worse performance on FNAME in cognitively healthy individuals were found related to higher amyloid beta (Aβ) burden measured with Positron-Emission-Tomography using 11C-PiB (PiB-PET). We previously reported normative data of a Spanish version of FNAME (S-FNAME) in cognitively healthy Spanish-speaking subjects. The aim of the present study was to determine whether performance on S-FNAME was associated with Aβ burden in subjective cognitive decline (SCD) individuals. 200 SCD subjects received neurological and neuropsychological assessments, including the S-FNAME and the Word List task from the Wechsler-Memory-Scale-III (WMS-III). Moreover, they received an MRI and (18)F-Florbetaben Positron-Emission-Tomography (FBB-PET) to measure Aβ burden. Three cognitive factor composites were derived for the episodic memory measures (face-name [SFN-N], face-occupation [SFN-O] and WMS-III) to determine whether episodic memory performance was related to Aβ deposition. Higher global Aβ deposition was significantly related to worse performance on SFN-N but not with SFN-O or WMS-III Composite. Moreover, worse SFN-N performance was significantly related to higher Aβ deposition in bilateral  Posterior Cingulate Cortex. The S-FNAME may be a promising neuropsychological tool for detecting SCD individuals with preclinical AD.

  View details for DOI 10.1038/s41598-018-21644-y

  View details for Web of Science ID 000426262400081

  View details for PubMedID 29491481

  View details for PubMedCentralID PMC5830648

• Patient Engagement: The Fundacio ACE Framework for Improving Recruitment and Retention in Alzheimer's Disease Research JOURNAL OF ALZHEIMERS DISEASE Boada, M., Santos-Santos, M. A., Rodriguez-Gomez, O., Alegret, M., Canabate, P., Lafuente, A., Abdelnour, C., Buendia, M., Jose de Dios, M., Morera, A., Sanabria, A., Campo, L., Ruiz, A., Tarraga, L. 2018; 62 (3): 1079-1090

  Abstract

  Alzheimer's disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació ACE to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies.

  View details for DOI 10.3233/JAD-170866

  View details for Web of Science ID 000427350400013

  View details for PubMedID 29562541

  View details for PubMedCentralID PMC5870013

• The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease JOURNAL OF ALZHEIMERS DISEASE Alegret, M., Pereto, M., Perez, A., Valero, S., Espinosa, A., Ortega, G., Hernandez, I., Mauleon, A., Rosende-Roca, M., Vargas, L., Rodriguez-Gomez, O., Abdelnour, C., Berthier, M. L., Bak, T. H., Ruiz, A., Tarraga, L., Boada, M. 2018; 62 (2): 611-619

  Abstract

  Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool.To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population.568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion.A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels).The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.

  View details for DOI 10.3233/JAD-170826

  View details for Web of Science ID 000426042100012

  View details for PubMedID 29480180

• Challenges for Service Robots - Requirements of Elderly Adults with cognitive Impairments FRONTIERS IN NEUROLOGY Korchut, A., Szklener, S., Abdelnour, C., Tantinya, N., Hernandez-Farigola, J., Carles Ribes, J., Skrobas, U., Grabowska-Aleksandrowicz, K., Szczesniak-Stanczyk, D., Rejdak, K. 2017; 8: 228

  Abstract

  We focused on identifying the requirements and needs of people suffering from Alzheimer disease and early dementia stages with relation to robotic assistants.Based on focus groups performed in two centers (Poland and Spain), we created surveys for medical staff, patients, and caregivers, including: functional requirements; human-robot interaction, the design of the robotic assistant and user acceptance aspects. Using Likert scale and analysis made on the basis of the frequency of survey responses, we identified users' needs as high, medium, and low priority.We gathered 264 completed surveys (100 from medical staff, 81 from caregivers, and 83 from potential users). Most of the respondents, almost at the same level in each of the three groups, accept robotic assistants and their support in everyday life. High level priority functional requirements were related to reacting in emergency situations (calling for help, detecting/removing obstacles) and to reminding about medication intake, about boiling water, turning off the gas and lights (almost 60% of answers). With reference to human-robot interaction, high priority was given to voice operated system and the capability of robotic assistants to reply to simple questions.Our results help in achieving better understanding of the needs of patients with cognitive impairments during home tasks in everyday life. This way of conducting the research, with considerations for the interests of three stakeholder groups in two autonomic centers with proven experience regarding the needs of our patient groups, highlights the importance of obtained results.

  View details for DOI 10.3389/fneur.2017.00228

  View details for Web of Science ID 000403264500002

  View details for PubMedID 28620342

  View details for PubMedCentralID PMC5451499

• Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort JOURNAL OF ALZHEIMERS DISEASE Kramberger, M. G., Auestad, B., Garcia-Ptacek, S., Abdelnour, C., Olmo, J., Walker, Z., Lemstra, A. W., Londos, E., Blanc, F., Bonanni, L., McKeith, I., Winblad, B., de Jong, F., Nobili, F., Stefanova, E., Petrova, M., Falup-Pecurariu, C., Rektorova, I., Bostantjopoulou, S., Biundo, R., Weintraub, D., Aarsland, D., E-DLB 2017; 57 (3): 787-795

  Abstract

  The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) patients.Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features.The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features.The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

  View details for DOI 10.3233/JAD-161109

  View details for Web of Science ID 000399460900013

  View details for PubMedID 28304294

  View details for PubMedCentralID PMC5392154

• Social Representation of Dementia: An Analysis of 5,792 Consecutive Cases Evaluated in a Memory Clinic JOURNAL OF ALZHEIMERS DISEASE Canabate, P., Martinez, G., Rosende-Roca, M., Moreno, M., Preckler, S., Valero, S., Sotolongo, O., Hernandez, I., Alegret, M., Ortega, G., Espinosa, A., Mauleon, A., Vargas, L., Rodriguez, O., Abdelnour, C., Sanchez, D., Martin, E., Ruiz, A., Tarraga, L., Boada, M. 2017; 58 (4): 1099-1108

  Abstract

  Different interpretations of cognitive impairment and dementia due to differences in health structures, such as cultural differences could affect the diagnosis and treatment of the condition. it is reasonable to expect that the social and family impact of the disease and coping strategies will differ among societies.The general aim of this study is to understand the social representations of dementia, its associated practices, and the effects they imply.People diagnosed with clinical dementia and their families were assessed from 2005 to 2015 in the memory clinic of the Fundació ACE, Institut Català de Neurociències Aplicades in Barcelona, Spain.9,898 people were examined and 5,792 were diagnosed with dementia. For those with a caregiver (71%), the decision-making fell on the person with dementia in 16.2% of the cases; and for those without a caregiver, in 26.4% of the cases the family did not perceive the deficits as a disease, which led to multiple risk situations (74.6%).The recognition of dementia as part of aging is common among families. Consequently, risk situations may arise and diagnosis and access to treatment may be delayed. The incorporation of a social appraisal to the diagnostic process is a necessity to evaluate these situations.

  View details for DOI 10.3233/JAD-161119

  View details for Web of Science ID 000404290200012

  View details for PubMedID 28527206

  View details for PubMedCentralID PMC5523907

• Impact of Recruitment Methods in Subjective Cognitive Decline JOURNAL OF ALZHEIMERS DISEASE Abdelnour, C., Rodriguez-Gomez, O., Alegret, M., Valero, S., Moreno-Grau, S., Sanabria, A., Hernandez, I., Rosende-Roca, M., Vargas, L., Mauleon, A., Sanchez, D., Espinosa, A., Ortega, G., Perez-Cordon, A., Diego, S., Gailhajanet, A., Guitart, M., Sotolongo-Grau, O., Ruiz, A., Tarraga, L., Boada, M. 2017; 57 (2): 625-632

  Abstract

  Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer's disease dementia, but little is known about its influence in subjective cognitive decline (SCD).To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD.We select and compare clinical and neuropsychological features, and frequency of APOE ɛ4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables.The OHI sample were mostly women (75.9% versus 64.5%, p < 0.05), with higher educational level (12.15 [3.71] versus 10.70 [3.80] years, p = 0.001), and more family history of dementia (138 [62.7%] versus 44 [41.5%], p < 0.001) than the MU sample. Also, the OHI sample showed better overall neuropsychological performance than the MU sample, and after a LRA, this trend continued in automatic response inhibition capacity, abstract reasoning, and recognition memory. We did not find differences in age, depression history, and/or APOE ɛ4 allele frequency.SCD subjects showed different demographic and neuropsychological characteristics depending on the recruitment method, which should be taken into account in the design of research studies with this target population.

  View details for DOI 10.3233/JAD-160915

  View details for Web of Science ID 000398725100023

  View details for PubMedID 28269773

• Alzheimer's disease cerebrospinal fluid biomarkers predict cognitive decline in lewy body dementia MOVEMENT DISORDERS Abdelnour, C., van Steenoven, I., Londos, E., Blanc, F., Auestad, B., Kramberger, M. G., Zetterberg, H., Mollenhauer, B., Boada, M., Aarsland, D., European DLB Consortium 2016; 31 (8): 1203-1208

  Abstract

  Alzheimer's disease pathologies are common in dementia with Lewy bodies, but their clinical relevance is not clear. CSF biomarkers amyloid beta 1-42, total tau, and tau phosphorylated at threonine 181 reflect Alzheimer's disease neuropathology antemortem. In PD, low CSF amyloid beta 1-42 predict long-term cognitive decline, but little is known about these biomarkers as predictors for cognitive decline in Lewy body dementia. The aim of this study was to assess whether Alzheimer's disease CSF biomarkers predict cognitive decline in Lewy body dementia.From a large European dementia with Lewy bodies multicenter study, we analyzed baseline Alzheimer's disease CSF biomarkers and serial MMSE (baseline and 1- and 2-year follow-up) in 100 patients with Lewy body dementia. Linear mixed-effects analyses, adjusted for sex, age, baseline MMSE, and education, were performed to model the association between CSF biomarkers and rate of cognitive decline measured with MMSE. An Alzheimer's disease CSF profile was defined as pathological amyloid beta 1-42 plus pathological total tau or phosphorylated tau.The Alzheimer's disease CSF profile, and pathological levels of amyloid beta 1-42, were associated with a more rapid decline in MMSE (2.2 [P < 0.05] and 2.9 points difference [P < 0.01], respectively). Higher total tau values showed a trend toward association without statistical significance (2.0 points difference; P = 0.064), whereas phosphorylated tau was not associated with decline.Reduced levels of CSF amyloid beta 1-42 were associated with more rapid cognitive decline in Lewy body dementia patients. Future prospective studies should include larger samples, centralized CSF analyses, longer follow-up, and biomarker-pathology correlation. © 2016 International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.26668

  View details for Web of Science ID 000382558800021

  View details for PubMedID 27296778

• Influence of Sampling and Recruitment Methods in Studies of Subjective Cognitive Decline JOURNAL OF ALZHEIMERS DISEASE Rodriguez-Gomez, O., Abdelnour, C., Jessen, F., Valero, S., Boada, M. 2015; 48: S99-S107

  Abstract

  Subjective cognitive decline (SCD) has been proposed as a marker of neurodegeneration in cognitively normal elderly. This idea is supported by the growing evidence that SCD is associated with Alzheimer's disease (AD) biomarkers and increases the risk of future cognitive impairment. Nevertheless, this evidence is not complete, since other studies have not found these associations. This discrepancy could have a methodological basis. It is well known that across the broad spectrum of degenerative disease from healthy controls to dementia, the research setting affects key characteristics of the sample such as age, educational level, or family history of dementia. However, virtually no studies have specifically tested the influence of sampling and recruitment methods in SCD research. Population-based samples are less biased and therefore they probably are more suitable for the study of memory complaints as a symptom at the population level. On the other hand, the memory clinic setting could introduce a set of biases that make these patients more likely to develop cognitive impairment. Thus, memory clinic would be the most cost-effective context in which to study the phenomenology of SCD due to AD and eventually recruit patients for secondary prevention trials. However, this general hypothesis needs to be tested. Studies that compare samples of patients with SCD from different settings are necessary. Sometimes it is difficult for patients with subtle forms of cognitive impairment to access specialized diagnostic centers. Based in our experience we state that Open House type initiatives may be useful for attracting these individuals to memory clinics.

  View details for DOI 10.3233/JAD-150189

  View details for Web of Science ID 000361963800010

  View details for PubMedID 26402087