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

Authors: Bartels, Claudia | Kögel, Anna | Schweda, Mark | Wiltfang, Jens | Pentzek, Michael | Schicktanz, Silke | Schneider, Anja

Article Type: Research Article

Abstract: Background: The National Institute of Aging and Alzheimer’s Association’s diagnostic recommendations for preclinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. Objective: We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. Methods: We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals …and memory clinics) in Germany. Results: From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42 , tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p ≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p  = 0.006), given that all CSF biomarkers were in the pathological range. Conclusion: Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed. Show more

Keywords: Alzheimer’s disease, biomarker, mild cognitive impairment, prediction, questionnaires, subjective cognitive decline, surveys

DOI: 10.3233/JAD-200794

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

Authors: Tan, Meng-Shan | Yang, Yu-Xiang | Wang, Hui-Fu | Xu, Wei | Tan, Chen-Chen | Zuo, Chuan-Tao | Dong, Qiang | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer’s disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms. Objective: Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status. Methods: We included 372 nondemented elderly from the Alzheimer’s Disease Neuroimaging Initiative cohort. …All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels. Results: Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42 , APOE ɛ 4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels. Conclusion: Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE, biomarker, cerebrospinal fluid, Mini-Mental State Examination, PET, tau

DOI: 10.3233/JAD-200124

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

Authors: Zhang, Zhihua | Sheng, Hongxia | Liao, Li | Xu, Chen | Zhang, Ang | Yang, Yang | Zhao, Long | Duan, Lian | Chen, Hu | Zhang, Bin

Article Type: Research Article

Abstract: Background: Mesenchymal stem cells-conditioned medium (MSC-CM) provides a promising cell-free therapy for Alzheimer’s disease (AD) mainly due to the paracrine of MSCs, but the precise mechanisms remain unclear. Studies suggests that mitochondrial dysfunction precedes the accumulation of amyloid-β plaques and neurofibrillary tangles, and involves in the onset and development of AD. Objective: In the present study, we evaluated the protective effects and explored the related-mitochondrial mechanisms of human umbilical cord derived MSC-CM (hucMSC-CM) in an AD model in vitro . Methods: To this end, an AD cellular model was firstly established by okadaic acid (OA)-treated SH-SY5Y …cells, and then treated by hucMSC-CM to assess the oxidative stress, mitochondrial function, apoptosis, AD-related genes, and signaling pathways. Results: hucMSC-CM significantly deceased tau phosphorylated at Thr181 (p181 -tau) level, which was increased in AD. hucMSC-CM also alleviated intracellular and mitochondrial oxidative stress in OA-treated SH-SY5Y cells. In addition, hucMSC-CM suppressed apoptosis and improved mitochondrial function in OA-treated SH-SY5Y cells. Flow cytometric analysis indicated that hucMSC-CM exerted the protective effects relying on or partly extracellular vesicle (EV) mitochondrial transfer from hucMSCs to OA-treated SH-SY5Y cells. Moreover, RNA sequencing data further demonstrated that hucMSC-CM regulated many AD-related genes, signaling pathways and mitochondrial function. Conclusion: These results indicated that MSC-CM or MSC-EVs containing abundant mitochondria may provide a novel potential therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, apoptosis, mesenchymal stem cell-conditioned medium, mitochondrial dysfunction, mitochondrial transfer

DOI: 10.3233/JAD-200686

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Ghilain, Matthieu | Hobeika, Lise | Lesaffre, Micheline | Schiaratura, Loris | Singh, Ashmita | Six, Joren | Huvent-Grelle, Dominique | Puisieux, François | Samson, Séverine

Article Type: Research Article

Abstract: Background: Music-based interventions appear to be efficient approaches to improve emotional, social, and cognitive functioning of patients with neurodegenerative diseases. Objective: Because benefits seem to increase with patient’s motor involvement, we studied sensorimotor synchronization (SMS) abilities of patients with cognitive impairments (Alzheimer’s disease, vascular and mixed dementia) and of patients with no evidence of cognitive impairments. More specifically, we compared the impact of a live performance by a musician to a video recording on SMS. Methods: SMS to a metronomic or a musical stimulus was assessed while patients watched a live musician or his pre-recorded video. …Results: SMS to a metronome was better than to music but this effect was modulated by the social context. While SMS to a metronome was better when facing a video than a live performance, there was no impact of social context on SMS to music. No group differences of SMS were found. Conclusion: The decrease in SMS to a metronome in a live performance may be due to social pressure. Such a pressure might be removed in pleasant social activities, like moving with music in a group, explaining the lack of effect on SMS to music. We found no performance differences in groups, suggesting relatively spared SMS in cognitively impaired patients. By showing that it is possible to encourage patients to synchronize with others, even when facing a video, our results indicate that SMS can be used as a relevant predictor in clinical trials and open up promising therapeutic options for isolated patients. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, dementia, motor activity, music therapy, social interaction

DOI: 10.3233/JAD-200521

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Gkioka, Mara | Schneider, Julia | Kruse, Andreas | Tsolaki, Magda | Moraitou, Despina | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: People with dementia (PwD) are frequently admitted to hospital settings. The lack of proper dementia knowledge, poor communication skills, negative attitudes toward dementia, and lack of confidence affects the quality of care, thus development of dementia trainings has increased. Nevertheless, literature regarding the effectiveness of training implementation is limited. Objective: The aim of this narrative synthesis is to 1) identify the characteristics of training programs and 2) explore the effectiveness of these training programs in everyday clinical practice. Methods: A systematic search in PubMed, PsycINFO, CINAHL, and Cochrane was conducted, including qualitative and quantitative peer-reviewed …studies. Holton’s evaluation model with its three outcome levels (learning, individual performance, and organizational results) was adopted. 14 studies were included. Results: The synthesis of the results was divided into two parts: 1) to describe the characteristics and content of trainings 2) to evaluate the effectiveness of training programs according to the three outcome levels of Holton’s model, taking into consideration its construct domains: ability, motivation, and environment. Learning outcomes were assessed in all selected studies: 13 studies observed changes in individual performance, four studies reported changes within the organizational level, and only five showed sustainable changes over time. Conclusion: Person-centered care (PCC) approaches, interactive and varied teaching methods, supporting conditions like champions, action plans, and setting care policies, are all characteristics of effective trainings. Successful programs should be sustainable over time, demonstrating positive outcomes across the organization. Based on current findings, there is a lack of adequate evaluation with regard to training programs on the organizational level. Show more

Keywords: Alzheimer’s disease, education, health facilities, literature synthesis, personnel, workforce development

DOI: 10.3233/JAD-200741

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2020

Authors: Liu, Kathy Y. | Costello, Harry | Reeves, Suzanne | Howard, Robert | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Agitation in Alzheimer’s disease (AD) has been hypothesized to be an expression of anxiety, but whether anxiety early in the course of dementia could be a risk factor for developing later agitation is unknown. Objective: We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to examine the longitudinal relationship between anxiety and incident agitation in individuals with a diagnosis of AD at baseline or during follow-up. Methods: Longitudinal neuropsychiatric symptom data from AD individuals who were agitation-free at study baseline (N  = 272) were analyzed using mixed effects regression models to test the longitudinal relationship between …baseline and incident anxiety with incident agitation. Results: Anxiety at baseline was not associated with subsequent agitation, but there was a positive linear relationship between incident anxiety and agitation over the study duration. Baseline apathy and delusions were consistently associated with subsequent agitation and greater disease severity and illness duration also appeared to be risk factors for agitation. Conclusion: Our findings support the concept that anxiety and agitation are likely to be distinct rather than equivalent constructs in mild-moderate AD. Future longitudinal cohort studies are needed to replicate these findings and further characterize potential risk factors for agitation, such as apathy and delusions. Show more

Keywords: Agitation, Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, anxiety, apathy, delusions

DOI: 10.3233/JAD-200516

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Hallab, Asma | Lange, Catharina | Apostolova, Ivayla | Özden, Cansu | Gonzalez-Escamilla, Gabriel | Klutmann, Susanne | Brenner, Winfried | Grothe, Michel J. | Buchert, Ralph | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Research in rodents identified specific neuron populations encoding information for spatial navigation with particularly high density in the medial part of the entorhinal cortex (ERC), which may be homologous with Brodmann area 34 (BA34) in the human brain. Objective: The aim of this study was to test whether impaired spatial navigation frequently occurring in mild cognitive impairment (MCI) is specifically associated with neurodegeneration in BA34. Methods: The study included baseline data of MCI patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative with high-resolution structural MRI, brain FDG PET, and complete visuospatial ability scores of the …Everyday Cognition test (VS-ECog) within 30 days of PET. A standard mask of BA34 predefined in MNI space was mapped to individual native space to determine grey matter volume and metabolic activity in BA34 on MRI and on (partial volume corrected) FDG PET, respectively. The association of the VS-ECog sum score with grey matter volume and metabolic activity in BA34, APOE4 carrier status, age, education, and global cognition (ADAS-cog-13 score) was tested by linear regression. BA28, which constitutes the lateral part of the ERC, was used as control region. Results: The eligibility criteria led to inclusion of 379 MCI subjects. The VS-ECog sum score was negatively correlated with grey matter volume in BA34 (β= –0.229, p  = 0.022) and age (β= –0.124, p  = 0.036), and was positively correlated with ADAS-cog-13 (β= 0.175, p  = 0.003). None of the other predictor variables contributed significantly. Conclusion: Impairment of spatial navigation in MCI is weakly associated with BA34 atrophy. Show more

Keywords: Entorhinal cortex, 18F-fluorodeoxyglucose, grid cells, magnetic resonance imaging, mild cognitive impairment, positron emission tomography, spatial navigation, volumetry

DOI: 10.3233/JAD-200520

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Juárez-Cedillo, Teresa | Gutiérrez-Gutiérrez, Lidia | Sánchez-Hurtado, Luis Alejandro | Martínez-Rodríguez, Nancy | Juarez-Cedillo, Enrique

Article Type: Research Article

Abstract: Background: Dementia is a persistent, progressive state of cognitive decline against which pharmacological intervention has a modest efficacy, reducing behavioral but not cognitive symptoms. Therefore, different non-pharmacological therapies have been developed; the most scientifically recognized are cognitive therapies that have improved cognitive function and daily life activities. Objective: To evaluate the effectiveness of a multicomponent cognitive stimulation therapy (SADEM) on cognitive and behavioral function and daily life activities in patients with mild stage dementia. Methods: Controlled clinical trial with pre- and post-intervention (12 months) and follow-up (24 months after) evaluations. Participants (67) diagnosed with mild dementia …were randomly assigned to intervention group (n  = 39) or control group (n  = 28). The intervention took place throughout one year and consisted of two weekly 90-minute sessions and one more a year after a monthly follow-up. Instruments were used to evaluate outcomes in cognitive, behavioral, and affective domains. Results: The results showed statistically significant differences, with improvement in the cognitive outcomes and the Dementia Index post-intervention (p  = 0.01). No progression of the disease was observed at the end of the study. Conclusion: The multicomponent intervention tested had positive effects on cognitive and behavioral functions and daily life activities in people with mild stage dementia, delaying progression for at least two years. Show more

Keywords: Cognitive stimulation therapy, dementia, functional cognition, multicomponent intervention, music therapy, SADEM

DOI: 10.3233/JAD-200574

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

Authors: Fields, Taylor N. | Mueller, Kimberly D. | Koscik, Rebecca L. | Johnson, Sterling C. | Okonkwo, Ozioma C. | Litovsky, Ruth Y.

Article Type: Research Article

Abstract: Background: Growing evidence suggests hearing loss is a risk factor for mild cognitive impairment and dementia, but few studies have examined its relationship to sub-clinical cognitive outcomes. Objective: To investigate the effect of self-reported hearing loss on longitudinal cognitive function in a risk-enriched cohort of clinically-unimpaired, late middle-aged adults. Methods: 579 participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) were included. Hearing status was determined via self-reported history of diagnosed hearing loss. Each participant with self-reported hearing loss was age- and sex-matched to two participants who never reported hearing loss using nearest-neighbor matching. Linear mixed-effects …models were used to examine associations between self-reported hearing loss and age-related cognitive trajectories with covariates of sex, literacy, and ethnicity, person-level random intercepts and age-related slopes. Cognitive outcomes encompassed measures of speed and flexibility, visuospatial memory, and verbal fluency. Results: Participants with self-reported hearing loss exhibited significantly poorer performance on a speed and flexibility factor score and single test of psychomotor speed and executive function, relative to participants who never reported hearing loss. There was no association between self-reported hearing loss and visuospatial memory or verbal fluency. Longitudinally, self-reported hearing loss was associated with less rapid decline in speed and flexibility and no difference in rate of decline for any other cognitive measure. Conclusion: Self-reported hearing loss was associated with poorer speed and flexibility but not with accelerated decline in any domain studied, contrary to previous findings. Further studies involving behavioral auditory measures in this cohort would clarify the robustness of these findings. Show more

Keywords: Alzheimer’s disease, cognition, cognitive impairment, executive function, hearing, hearing loss, longitudinal studies

DOI: 10.3233/JAD-200701

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Crocco, Elizabeth | Curiel-Cid, Rosie E. | Kitaigorodsky, Marcela | González-Jiménez, Christian J. | Zheng, Diane | Duara, Ranjan | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) is an increasingly utilized cognitive stress test designed to identify early cognitive changes associated with incipient neurodegenerative disease. Objective: To examine previously derived cut-points for cognitively unimpaired older adults that were suggestive of performance impairment on multiple subscales of the LASSI-L. These cut-points were applied to a new sample of older adults who were cognitive healthy controls (HC: n  = 26) and those on the Alzheimer’s disease (AD) continuum from early stage mild cognitive impairment (E-MCI: n  = 28), late stage MCI (L-MCI: n-18) to mild AD (AD: n  = 27). …Methods: All participants were administered the LASSI-L. All cognitively impaired participants were PET amyloid positive which likely reflects underlying AD neuropathology, while cognitively normal counterparts were deemed to have amyloid negative scans. Results: There was a monotonic relationship between the number of deficits on LASSI-L subscales and independent classification of study groups with greater severity of cognitive impairment. Importantly, taken together, impairment on maximum learning ability and measures of proactive semantic interference (both reflected by cued recall and intrusion errors) correctly classified 74.1% of EMCI, 94.4% of LMCI, and 96.3% of AD. Only 7.7% of HC were incorrectly classified as having impairments. Conclusion: A modest number of LASSI-L subscales taking approximately 8 minutes to administer, had excellent discriminative ability using established cut-offs among individuals with presumptive stages of AD. This has potential implications for both clinical practice and clinical research settings targeting AD during early prodromal stages. Show more

Keywords: Amyloid, biomarkers, cognitive screening, intrusion errors, mild cognitive impairment, neuroimaging, preclinical Alzheimer’s disease, semantic interference, structural MRI

DOI: 10.3233/JAD-200790

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020