Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Junquera Fernández, Almudena | García-Zamora, Estefanía | Olazarán Rodríguez, Javier | Parra Rodríguez, Mario A. | Fernández-Guinea, Sara

Article Type: Research Article

Abstract: Background: Recent research pointed to executive dysfunction as a potential early predictor of the progression of mild cognitive impairment (MCI)–dementia in Alzheimer’s clinical syndrome (ACS). Such cognitive impairments account for functional impairments in instrumental activities of daily living (IADL). Objective: The present study analyzes the contributions of executive functions to predict MCI–dementia progression in ACS. Methods: We assessed 145 participants, 51 cognitively unimpaired and 94 MCI. The latter were divided using the traditional, memory-based MCI classification (single domain amnestic, multidomain amnestic, and non-amnestic). Eight tests assessing executive functions were administered at baseline and at 1-year follow-up, …together with cognitive screening tools and IADL measures. MCI patients were reclassified based on the outcomes from a K-mean cluster analysis which identified three groups. A simple lineal regression model was used to examine whether the classification based on executive functioning could more accurately predict progression to dementia a year later. Results: Clusters based on executive function deficits explained a significant proportion of the variance linked to MCI–dementia conversion, even after controlling for the severity of MCI at baseline (F (1, 68) = 116.25, p  = 0.000, R2  = 0.63). Classical memory-based MCI classification failed to predict such a conversion (F (1, 68) = 5.09, p  = 0.955, R2  = 0.07). Switching, categories generation, and planning were the executive functions that best distinguished between MCI converters and stable. Conclusion: MCI with a dysexecutive phenotype significantly predicts conversion to dementia in ACS a year later. Switching abilities and verbal fluency (categories) must be evaluated in MCI patients to assess risk of future dementia. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognitive dysfunction, executive function, longitudinal studies

DOI: 10.3233/JAD-200586

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: McKeown, Alex | Turner, Andrew | Angehrn, Zuzanna | Gove, Dianne | Ly, Amanda | Nordon, Clementine | Nelson, Mia | Tochel, Claire | Mittelstadt, Brent | Keenan, Alex | Smith, Michael | Singh, Ilina

Article Type: Research Article

Abstract: Background: Dementia has been described as the greatest global health challenge in the 21st century on account of longevity gains increasing its incidence, escalating health and social care pressures. These pressures highlight ethical, social, and political challenges about healthcare resource allocation, what health improvements matter to patients, and how they are measured. This study highlights the complexity of the ethical landscape, relating particularly to the balances that need to be struck when allocating resources; when measuring and prioritizing outcomes; and when individual preferences are sought. Objective: Health outcome prioritization is the ranking in order of desirability or importance …of a set of disease-related objectives and their associated cost or risk. We analyze the complex ethical landscape in which this takes place in the most common dementia, Alzheimer’s disease. Methods: Narrative review of literature published since 2007, incorporating snowball sampling where necessary. We identified, thematized, and discussed key issues of ethical salience. Results: Eight areas of ethical salience for outcome prioritization emerged: 1) Public health and distributive justice, 2) Scarcity of resources, 3) Heterogeneity and changing circumstances, 4) Knowledge of treatment, 5) Values and circumstances, 6) Conflicting priorities, 7) Communication, autonomy and caregiver issues, and 8) Disclosure of risk. Conclusion: These areas highlight the difficult balance to be struck when allocating resources, when measuring and prioritizing outcomes, and when individual preferences are sought. We conclude by reflecting on how tools in social sciences and ethics can help address challenges posed by resource allocation, measuring and prioritizing outcomes, and eliciting stakeholder preferences. Show more

Keywords: Alzheimer’s disease, dementia, ethics, health priorities

DOI: 10.3233/JAD-191300

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Tomoto, Tsubasa | Tarumi, Takashi | Chen, Jason | Pasha, Evan P. | Cullum, C. Munro | Zhang, Rong

Article Type: Research Article

Abstract: Background: Cerebral blood flow (CBF) is sensitive to changes in arterial CO2 , referred to as cerebral vasomotor reactivity (CVMR). Whether CVMR is altered in patients with amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer disease (AD), is unclear. Objective: To determine whether CVMR is altered in aMCI and is associated with cognitive performance. Methods: Fifty-three aMCI patients aged 55 to 80 and 22 cognitively normal subjects (CN) of similar age, sex, and education underwent measurements of CBF velocity (CBFV) with transcranial Doppler and end-tidal CO2 (EtCO2 ) with capnography during hypocapnia (hyperventilation) …and hypercapnia (rebreathing). Arterial pressure (BP) was measured to calculate cerebrovascular conductance (CVCi) to normalize the effect of changes in BP on CVMR assessment. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and neuropsychological tests focused on memory (Logical Memory, California Verbal Learning Test) and executive function (Delis-Kaplan Executive Function Scale; DKEFS). Results: At rest, CBFV and MMSE did not differ between groups. CVMR was reduced by 13% in CBFV% and 21% in CVCi% during hypocapnia and increased by 22% in CBFV% and 20% in CVCi% during hypercapnia in aMCI when compared to CN (all p  < 0.05). Logical Memory recall scores were positively correlated with hypocapnia (r  = 0.283, r  = 0.322, p  < 0.05) and negatively correlated with hypercapnic CVMR measured in CVCi% (r  = –0.347, r  = –0.446, p  < 0.01). Similar correlations were observed in D-KEFS Trail Making scores. Conclusion: Altered CVMR in aMCI and its associations with cognitive performance suggests the presence of cerebrovascular dysfunction in older adults who have high risks for AD. Show more

Keywords: Cerebral blood flow, cerebral vasomotor reactivity, hypercapnia, hypocapnia, mild cognitive impairment, transcranial Doppler

DOI: 10.3233/JAD-200194

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Palacios, Natalia | Lee, Jong Soo | Scott, Tammy | Kelly, Rachel S. | Bhupathiraju, Shilpa N. | Bigornia, Sherman J. | Tucker, Katherine L.

Article Type: Research Article

Abstract: Background: Minorities, including mainland Puerto Ricans, are impacted disproportionally by Alzheimer’s disease (AD), dementia, and cognitive decline. Studying blood metabolomics in this population has the potential to probe the biological underpinnings of this health disparity. Objective: We performed a comprehensive analysis of circulating plasma metabolites in relation to cognitive function in 736 participants from the Boston Puerto Rican Health Study (BPRHS) who underwent untargeted mass-spectrometry based metabolomics analysis and had undergone a battery of in-person cognitive testing at baseline. Methods: After relevant exclusions, 621 metabolites were examined. We used multivariable regression, adjusted for age, sex, education, …apolipoprotein E genotype, smoking, and Mediterranean dietary pattern, to identify metabolites related to global cognitive function in our cohort. LASSO machine learning was used in a complementary analysis to identify metabolites that could discriminate good from poor extremes of cognition. We also conducted sensitivity analyses: restricted to participants without diabetes, and to participants with good adherence to Mediterranean diet. Results: Of 621 metabolites, FDR corrected (p  < 0.05) multivariable linear regression identified 3 metabolites positively, and 10 negatively, associated with cognitive function in the BPRHS. In a combination of FDR-corrected linear regression, logistic regression regularized via LASSO, and sensitivity analyses restricted to participants without diabetes, and with good adherence to the Mediterranean diet, β-cryptoxanthin plasma concentration was consistently associated with better cognitive function and N-acetylisoleucine and tyramine O-sulfate concentrations were consistently associated with worse cognitive function. Conclusion: This untargeted metabolomics study identified potential biomarkers for cognitive function in a cohort of Puerto Rican older adults. Show more

Keywords: Cognitive function, diabetes, Puerto Ricans, metabolomics

DOI: 10.3233/JAD-200040

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Breuza, Lionel | Arighi, Cecilia N. | Argoud-Puy, Ghislaine | Casals-Casas, Cristina | Estreicher, Anne | Famiglietti, Maria Livia | Georghiou, George | Gos, Arnaud | Gruaz-Gumowski, Nadine | Hinz, Ursula | Hyka-Nouspikel, Nevila | Kramarz, Barbara | Lovering, Ruth C. | Lussi, Yvonne | Magrane, Michele | Masson, Patrick | Perfetto, Livia | Poux, Sylvain | Rodriguez-Lopez, Milagros | Stoeckert, Christian | Sundaram, Shyamala | Wang, Li-San | Wu, Elizabeth | Orchard, Sandra | IMEx Consortium, UniProt Consortium

Article Type: Research Article

Abstract: Background: The analysis and interpretation of data generated from patient-derived clinical samples relies on access to high-quality bioinformatics resources. These are maintained and updated by expert curators extracting knowledge from unstructured biological data described in free-text journal articles and converting this into more structured, computationally-accessible forms. This enables analyses such as functional enrichment of sets of genes/proteins using the Gene Ontology, and makes the searching of data more productive by managing issues such as gene/protein name synonyms, identifier mapping, and data quality. Objective: To undertake a coordinated annotation update of key public-domain resources to better support Alzheimer’s disease …research. Methods: We have systematically identified target proteins critical to disease process, in part by accessing informed input from the clinical research community. Results: Data from 954 papers has been added to the UniProtKB, Gene Ontology, and the International Molecular Exchange Consortium (IMEx) databases, with 299 human proteins and 279 orthologs updated in UniProtKB. 7,45 binary interactions were added to the IMEx human molecular interaction dataset. Conclusion: This represents a significant enhancement in the expert curated data pertinent to Alzheimer’s disease available in a number of biomedical databases. Relevant protein entries have been updated in UniProtKB and concomitantly in the Gene Ontology. Molecular interaction networks have been significantly extended in the IMEx Consortium dataset and a set of reference protein complexes created. All the resources described are open-source and freely available to the research community and we provide examples of how these data could be exploited by researchers. Show more

Keywords: Alzheimer’s disease, Cytoscape network analysis, data curation, database, neurobiology, protein

DOI: 10.3233/JAD-200206

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Vidoni, Eric D. | Kamat, Ashwini | Gahan, William P. | Ourso, Victoria | Woodard, Kaylee | Kerwin, Diana R. | Binder, Ellen F. | Burns, Jeffrey M. | Cullum, Munro | Hynan, Linda S. | Vongpatanasin, Wanpen | Zhu, David C. | Zhang, Rong | Keller, Jeffrey N.

Article Type: Research Article

Abstract: Background: Little is known about the prevalence of polypharmacy, the taking of five or more medications a day, in older adults with specific dementia risk factors. Objective: To examine the prevalence of polypharmacy in participants at baseline in a vascular risk reduction focused Alzheimer’s disease (rrAD) trial targeting older patients with hypertension and elevated dementia risk. Methods: We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk. Medications were identified in a structured interview process with an onsite pharmacist or qualified designee. Polypharmacy was defined …as use of five or more medications on a regular basis. Descriptive analyses were conducted on the sample as well as direct comparisons of subgroups of individuals with hypertension, diabetes, and hyperlipidemia. Results: The 514 rrAD participants, mean age 68.8 (standard deviation [sd] 6), reported taking different combinations of 472 unique medications at their baseline visit. The median number of medications taken by participants was eight [Range 0–21], with 79.2% exhibiting polypharmacy (n  = 407). Sites differed in their prevalence of polypharmacy, χ 2 (3) = 56.0, p  < 0.001. A nearly identical percentage of the 2,077 prescribed (51.8%) and over the counter (48.2%) medications were present in the overall medication profile. The presence of diabetes (87.5%), hyperlipidemia (88.2%), or both (97.7%) was associated with a higher prevalence of polypharmacy than participants who exhibited hypertension in the absence of either of these conditions (63.2%), χ 2 (3) = 35.8, p  < 0.001. Conclusion: Participants in a dementia risk study had high levels of polypharmacy, with the co-existence of diabetes or hyperlipidemia associated with a greater prevalence of polypharmacy as compared to having hypertension alone. Show more

Keywords: Alzheimer’s disease, dementia, hypertension, inappropriate medication, polypharmacy, risk factor

DOI: 10.3233/JAD-200122

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Gárate-Vélez, Lorena | Escudero-Lourdes, Claudia | Salado-Leza, Daniela | González-Sánchez, Armando | Alvarado-Morales, Ildemar | Bahena, Daniel | Labrada-Delgado, Gladis Judith | Rodríguez-López, José Luis

Article Type: Research Article

Abstract: Background: Iron nanoparticles, mainly in magnetite phase (Fe3 O4 NPs), are released to the environment in areas with high traffic density and braking frequency.Fe3 O4 NPs were found in postmortem human brains and are assumed to get directly into the brain through the olfactory nerve. However, these pollution-derived NPs may also translocate from the lungs to the bloodstream and then, through the blood-brain barrier (BBB), into the brain inducing oxidative and inflammatory responses that contribute to neurodegeneration. Objective: To describe the interaction and toxicity of pollution-derived Fe3 O4 NPs on primary rat brain microvascular endothelial …cells (rBMECs), main constituents of in vitro BBB models. Methods: Synthetic bare Fe3 O4 NPs that mimic the environmental ones (miFe3 O4 ) were synthesized by co-precipitation and characterized using complementary techniques. The rBMECs were cultured in Transwell® plates. The NPs-cell interaction was evaluated through transmission electron microscopy and standard colorimetric in vitro assays. Results: The miFe3 O4 NPs, with a mean diameter of 8.45±0.14 nm, presented both magnetite and maghemite phases, and showed super-paramagnetic properties. Results suggest that miFe3 O4 NPs are internalized by rBMECs through endocytosis and that they are able to cross the cells monolayer. The lowest miFe3 O4 NPs concentration tested induced mid cytotoxicity in terms of 1) membrane integrity (LDH release) and 2) metabolic activity (MTS transformation). Conclusion: Pollution-derived Fe3 O4 NPs may interact and cross the microvascular endothelial cells forming the BBB and cause biological damage. Show more

Keywords: Blood-brain barrier, cytotoxicity, in vitro , magnetite nanoparticles

DOI: 10.3233/JAD-190929

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Sheng, Can | Sun, Yu | Wang, Min | Wang, Xiaoni | Liu, Yi | Pang, Dongqing | Liu, Jiaqi | Bi, Xiaoxia | Du, Wenying | Zhao, Mingyan | Li, Yuxia | Li, Xiaobo | Jiang, Jiehui | Han, Ying

Article Type: Research Article

Abstract: Background: Visual rating scales for medial temporal lobe atrophy (MTA) and posterior atrophy (PA) have been reported to be useful for Alzheimer’s disease diagnosis in routine clinical practice. Objective: To investigate the efficacy of combined MTA and PA visual rating scales to discriminate amnestic mild cognitive impairment (aMCI) patients from healthy controls. Methods: This study included T1-weighted MRI images from two different cohorts. In the first cohort, we recruited 73 patients with aMCI and 48 group-matched cognitively normal controls for training and validation. Visual assessments of MTA and PA were carried out for each participant. Global …gray matter volume and density were estimated using voxel-based morphometry analysis as the objective reference. We investigated the discriminative power of a single visual rating scale and the combination of the MTA and PA rating scales for identifying aMCI. The second cohort, consisting of 33 aMCI patients and 45 controls, was used to verify the reliability of the visual assessments. Results: Compared with the single visual rating scale, the combination of the MTA and PA exhibited the best discriminative power, with an AUC of 0.818±0.041, which was similar to the diagnostic accuracy of the gray matter volumetric measures. The discriminative power of the combined MTA and PA was verified in the second cohort (AUC 0.824±0.058). Conclusion: The combined MTA and PA rating scales demonstrated practical diagnostic value for distinguishing aMCI patients from controls, suggesting its potential to serve as a convenient and reproducible method to assess the degree of atrophy in clinical settings. Show more

Keywords: Magnetic resonance imaging, medial temporal lobe atrophy, mild cognitive impairment, posterior atrophy, visual rating scales

DOI: 10.3233/JAD-200016

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Lombardi, Gemma | Pupi, Alberto | Bessi, Valentina | Polito, Cristina | Padiglioni, Sonia | Ferrari, Camilla | Lucidi, Giulia | Berti, Valentina | De Cristofaro, Maria Teresa | Piaceri, Irene | Bagnoli, Silvia | Nacmias, Benedetta | Sorbi, Sandro

Article Type: Research Article

Abstract: Background: Discordance among amyloid biomarkers is a challenge to overcome in order to increase diagnostic accuracy in dementia. Objectives: 1) To verify that cerebrospinal fluid (CSF) Aβ42 /Aβ40 ratio (AβR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aβ42 ; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AβR and Amy-PET results; 3) to define the suspected underlying pathology of discordant cases using in vivo biomarkers. Method: We retrospectively enrolled 39 cognitively impaired participants in which neuropsychological tests, apolipoprotein …E genotype determination, TC/MRI, FDG-PET, Amy-PET, and CSF analysis had been performed. In all cases, CSF analysis was repeated using the automated Lumipulse method. In discordant cases, FDG-PET scans were evaluated visually and using automated classifiers. Results: CSF AβR better agreed with Amy-PET compared to CSF Aβ42 (Cohen’s K 0.431 versus 0.05). Comparisons among groups did not show any difference in clinical characteristics except for age at symptoms onset that was higher in the 6 discordant cases with abnormal CSF AβR values and negative Amy-PET (CSF AβR+/AmyPET–). FDG-PET and all CSF markers (Aβ42 , AβR, p-Tau, t-Tau) were suggestive of Alzheimer’s disease (AD) in 5 of these 6 cases. Conclusion: 1) CSF AβR is the CSF amyloid marker that shows the better level of agreement with Amy-PET results; 2) The use of FDG-PET and CSF-Tau markers in CSFAβR+/Amy-PET–discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AβR and negative Amy-PET in symptomatic aged AD patients could be due to the variability in plaques conformation and a negative Amy-PET scan cannot be always sufficient to rule out AD. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, diagnosis, PET scan

DOI: 10.3233/JAD-200119

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Luiu, Anna Laura | Favez, Nicolas | Betrancourt, Mireille | Szilas, Nicolas | Ehrler, Frederic

Article Type: Research Article

Abstract: Background: Family caregivers of people with Alzheimer’s disease are the most important support in concrete personal and economic terms. Family dynamics play a fundamental role in the provision of informal caregiving benefits. Objective: This review aims to identify factors related to the family caregiving of relatives with Alzheimer’s disease, taking specifically into account the construct of coping and expressed emotion. Methods: This is a systematic review including articles selected using search terms including “caregivers,” “Alzheimer’s,” “family,” and “relationship” in research databases. Findings were synthesized and categorized into themes. Results: A total of 454 abstracts …were identified. Following screening, lateral searches, and quality appraisal, 36 studies were included for synthesis. A total of 5 themes were identified: burden; demographics; coping strategies; caregiver mental health; and family dynamics and expressed emotions. Conclusion: The quality and level of evidence supporting each theme varied. We need further research into family dynamics ameliorating the caregiving and how to measure it. Show more

Keywords: Alzheimer’s disease, family caregivers, family relationship, systematic review

DOI: 10.3233/JAD-200125

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020