Journal of Alzheimer's Disease - Volume 87, issue 2

Authors: Sáez de Asteasu, Mikel L. | Cuevas-Lara, Cesar | García-Hermoso, Antonio | Ramírez-Vélez, Robinson | Martínez-Velilla, Nicolás | Zambom-Ferraresi, Fabricio | Cadore, Eduardo Lusa | Izquierdo, Mikel

Article Type: Systematic Review

Abstract: Background: Acute care hospitalization increases the likelihood of developing cognitive impairment and delirium in older adults. Objective: To summarize evidence about the effectiveness of exercise and physical rehabilitation interventions on the incidence of delirium and cognitive impairment in acutely hospitalized older patients. Methods: Relevant articles were systematically searched (PubMed, Web of Science, and CINHAL databases) until 26 August 2021. Randomized and nonrandomized controlled trials of in-hospital physical exercise interventions and rehabilitation programs compared to usual care performed for older patients (> 65 years) hospitalized for an acute medical condition were selected. The primary endpoints were changes in …the incidence of delirium and cognition during acute hospitalization. The secondary endpoints included functional independence, psychological measures, well-being status, length of hospital stay, transfer after discharge, fall occurrence, hospital readmissions, and mortality rate. The endpoints were evaluated at different time points (at admission, at discharge, and after discharge). Results: Eleven studies from 8 trials (n  = 3,646) were included. The methodological quality of the studies was mostly high. None of the studies reported any adverse events related to the intervention. Early rehabilitation improved cognitive function at 3 months postdischarge (Hedge’s g  = 0.33, 95% confidence interval [CI] 0.19 to 0.46, p  < 0.001). No between-group differences were found for incident delirium and cognitive impairment during hospitalization (all p  > 0.05). Conclusion: In-hospital physical exercise and early rehabilitation programs seem to be safe and effective interventions for enhancing cognitive function after discharge in older patients hospitalized for an acute medical condition. However, no potential benefits were obtained over usual hospital care for the incidence of delirium. Show more

Keywords: Physical exercise, rehabilitation, cognitive impairment, delirium, hospitalized, older adults

DOI: 10.3233/JAD-220103

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 503-517, 2022

Authors: González Cordero, Elisa Marina | Cuevas-Budhart, Miguel Angel | Pérez Morán, Diana | Trejo Villeda, Miguel Angel | Gomez-del-Pulgar Gª-Madrid, Mercedes

Article Type: Systematic Review

Abstract: Background: In recent years, scientific research on the gut microbiota and their relationship with some diseases, including neurological ones, has notably increased. As a result of these investigations, the so-called gut-brain axis arises. Despite its influence on the evolution and development of cognitive impairment, the gut-brain axis is little defined and demonstrated. Objective: To provide the best scientific evidence available on the relationship between the gut microbiota and Alzheimer’s disease. Method: Systematic and narrative review of the information generated in the last 5 years in national and international databases, in English and Spanish. Results: …Eight observational studies were selected, carried out in humans and, therefore, suitable for inclusion in this review. Conclusion: The results of these studies support the hypothesis that there is a relationship between the gut microbiota and cognitive disorders through the gut-brain axis. However, today, there is a substantial lack of human studies, especially clinical trials, which makes it difficult to formulate clinical recommendations on this topic. Show more

Keywords: Alzheimer’s disease, gut-brain axis, gut microbiome, microbiota, Parkinson’s disease

DOI: 10.3233/JAD-215224

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 519-528, 2022

Authors: Xolalpa-Cueva, Lorena | García-Carlos, Carlos Antonio | Villaseñor-Zepeda, Rocío | Orta-Salazar, Erika | Díaz-Cintra, Sofia | Peña-Ortega, Fernando | Perry, George | Mondragón-Rodríguez, Siddhartha

Article Type: Research Article

Abstract: Background: Tau hyperphosphorylation at several sites, including those close to its microtubule domain (MD), is considered a key pathogenic event in the development of tauopathies. Nevertheless, we recently demonstrated that at the very early disease stage, tau phosphorylation (pTau) at MD sites promotes neuroprotection by preventing seizure-like activity. Objective: To further support the notion that very early pTau is not detrimental, the present work evaluated the young rTg4510 mouse model of tauopathy as a case study. Thus, in mice at one month of age (PN30-35), we studied the increase of pTau within the hippocampal area as well as …hippocampal and locomotor function. Methods: We used immunohistochemistry, T-maze, nesting test, novel object recognition test, open field arena, and electrophysiology. Results: Our results showed that the very young rTg4510 mouse model has no detectable changes in hippocampal dependent tasks, such as spontaneous alternation and nesting, or in locomotor activity. However, at this very early stage the hippocampal neurons from PN30-35 rTg4510 mice accumulate pTau protein and exhibit changes in hippocampal oscillatory activity. Moreover, we found a significant reduction in the somatic area of pTau positive pyramidal and granule neurons in the young rTg4510 mice. Despite this, improved memory and increased number of dendrites per cell in granule neurons was found. Conclusion: Altogether, this study provides new insights into the early pathogenesis of tauopathies and provides further evidence that pTau remodels hippocampal function and morphology. Show more

Keywords: Alzheimer’s disease, hyperphosphorylation, memory, oscillatory activity, tau, tauopathies

DOI: 10.3233/JAD-215186

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 529-543, 2022

Authors: Wolfsgruber, Steffen | Kleineidam, Luca | Weyrauch, Anne-Sophie | Barkhoff, Miriam | Röske, Sandra | Peters, Oliver | Preis, Lukas | Gref, Daria | Spruth, Eike Jakob | Altenstein, Slawek | Priller, Josef | Fließbach, Klaus | Schneider, Anja | Wiltfang, Jens | Bartels, Claudia | Jessen, Frank | Maier, Franziska | Düzel, Emrah | Metzger, Coraline | Glanz, Wenzel | Buerger, Katharina | Janowitz, Daniel | Perneczky, Robert | Rauchmann, Boris-Stephan | Kilimann, Ingo | Teipel, Stefan | Laske, Christoph | Munk, Matthias H. | Roy, Nina | Spottke, Annika | Ramirez, Alfredo | Heneka, Michael T. | Brosseron, Frederic | Wagner, Michael | on behalf of the DELCODE study group

Article Type: Research Article

Abstract: Background: It is unclear whether subjective cognitive decline (SCD) is a relevant clinical marker of incipient Alzheimer’s disease (AD) and future cognitive deterioration in individuals with a family history of AD (FHAD). Objective: To investigate the association of SCD with cross-sectional cerebrospinal fluid (CSF) AD biomarker levels and cognitive decline in cognitively normal older adults with or without a first-degree FHAD. Methods: We analyzed data from cognitively normal individuals with first-degree FHAD (n  = 82 “AD relatives”; mean age: 65.7 years (SD = 4.47); 59% female) and a similar group of n  =  236 healthy controls without FHAD from …the DELCODE study. We measured SCD with an in-depth structured interview from which we derived a SCD score, capturing features proposed to increase likelihood of underlying AD (“SCD-plus score”). We tested whether higher SCD-plus scores were associated with more pathological CSF AD biomarker levels and cognitive decline over time and whether this association varied by group. Results: AD relatives showed higher SCD-plus scores than healthy controls and more cognitive decline over time. Higher SCD-plus scores also related stronger to cognitive change and abnormal CSF AD biomarker levels in the AD relatives as compared to the healthy controls group. Conclusion: Quantification of specific SCD features can provide further information on the likelihood of early AD pathology and cognitive decline among AD relatives. FHAD and SCD appear as synergistically acting enrichment strategies in AD research, the first one as a permanent indicator of genetic risk, the latter one as a correlate of disease progression. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, family history, subjective cognitive decline

DOI: 10.3233/JAD-215416

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 545-555, 2022

Authors: Ge, Xinting | Qiao, Yuchuan | Choi, Jiyoon | Raman, Rema | Ringman, John M. | Shi, Yonggang | for Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) individuals with neuropsychiatric symptoms (NPS) are more likely to develop dementia. Objective: We sought to understand the relationship between neuroimaging markers such as tau pathology and cognitive symptoms both with and without the presence of NPS during the prodromal period of Alzheimer’s disease. Methods: A total of 151 MCI subjects with tau positron emission tomographic (PET) scanning with 18 F AV-1451, amyloid-β (Aβ) PET scanning with florbetapir or florbetaben, magnetic resonance imaging, and cognitive and behavioral evaluations were selected from the Alzheimer’s Disease Neuroimaging Initiative. A 4-group division approach was proposed …using amyloid (A–/A+) and behavior (B–/B+) status: A–B–, A–B+, A+B–, and A+B+. Pearson’s correlation test was conducted for each group to examine the association between tau deposition and cognitive performance. Results: No statistically significant association between tau deposition and cognitive impairment was found for subjects without behavior symptoms in either the A–B–or A+B–groups after correction for false discovery rate. In contrast, tau deposition was found to be significantly associated with cognitive impairment in entorhinal cortex and temporal pole for the A–B+ group and nearly the whole cerebrum for the A+B+ group. Conclusion: Enhanced associations between tauopathy and cognitive impairment are present in MCI subjects with behavior symptoms, which is more prominent in the presence of elevated amyloid pathology. MCI individuals with NPS may thus be at greater risk for further cognitive decline with the increase of tau deposition in comparison to those without NPS. Show more

Keywords: Alzheimer’s disease, cognitive impairment, neuropsychiatric symptoms, tau-PET imaging

DOI: 10.3233/JAD-215555

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 557-568, 2022

Authors: Krause-Sorio, Beatrix | Siddarth, Prabha | Kilpatrick, Lisa | Milillo, Michaela M. | Aguilar-Faustino, Yesenia | Ercoli, Linda | Narr, Katherine L. | Khalsa, Dharma S. | Lavretsky, Helen

Article Type: Research Article

Abstract: Background: Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer’s disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations, and modulated brain connectivity in older adults with mild cognitive impairment. Objective: In this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRFs following three months of yoga compared to memory enhancement training (MET). Methods: Eleven women (mean age = 61.45, SD = 6.58) with CVRF and SCD completed twelve weeks of Kundalini Yoga and …Kirtan Kriya (KY + KK) while eleven women (mean age = 64.55, SD = 6.41) underwent MET. Anxiety, resilience, stress, and depression were assessed at baseline and 12 weeks, as were T1-weighted MRI scans (Siemens 3T Prisma scanner). We used Freesurfer 6.0 and tested group differences in GMV change, applying Monte-Carlo simulations with alpha = 0.05. Region-of-interest analysis was performed for hippocampus and amygdala. Results: Compared to KY + KK, MET showed reductions in GMV in left prefrontal, pre- and post-central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections. Conclusion: Yoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups. Show more

Keywords: Brain, cardiovascular risk, gray matter, Kirtan Kriya, Kundalini, memory, memory training, mind-body, MRI, prevention, women, yoga

DOI: 10.3233/JAD-215563

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 569-581, 2022

Authors: Dobromyslin, Vitaly I. | Megherbi, Dalila B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Structural brain imaging metrics and gene expression biomarkers have previously been used for Alzheimer’s disease (AD) diagnosis and prognosis, but none of these studies explored integration of imaging and gene expression biomarkers for predicting mild cognitive impairment (MCI)-to-AD conversion 1-2 years into the future. Objective: We investigated advantages of combining gene expression and structural brain imaging features for predicting MCI-to-AD conversion. Selection of the differentially expressed genes (DEGs) for classifying cognitively normal (CN) controls and AD patients was benchmarked against previously reported results. Methods: The current work proposes integrating brain imaging and blood gene expression …data from two public datasets (ADNI and ANM) to predict MCI-to-AD conversion. A novel pipeline for combining gene expression data from multiple platforms is proposed and evaluated in the two independents patient cohorts. Results: Combining DEGs and imaging biomarkers for predicting MCI-to-AD conversion yielded 0.832-0.876 receiver operating characteristic (ROC) area under the curve (AUC), which exceeded the 0.808-0.840 AUC from using the imaging features alone. With using only three DEGs, the CN versus AD predictive model achieved 0.718, 0.858, and 0.873 cross-validation AUC for the ADNI, ANM1, and ANM2 datasets. Conclusion: For the first time we show that combining gene expression and imaging biomarkers yields better predictive performance than using imaging metrics alone. A novel pipeline for combining gene expression data from multiple platforms is proposed and evaluated to produce consistent results in the two independents patient cohorts. Using an improved feature selection, we show that predictive models with fewer gene expression probes can achieve competitive performance. Show more

Keywords: Alzheimer’s disease, gene expression, MCI-to-AD conversion, predictive model

DOI: 10.3233/JAD-215640

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 583-594, 2022

Authors: Ichimata, Shojiro | Yoshida, Koji | Visanji, Naomi P. | Lang, Anthony E. | Nishida, Naoki | Kovacs, Gabor G.

Article Type: Research Article

Abstract: Background: Down syndrome (DS) is frequently associated with Alzheimer��s disease (AD)-related neuropathological changes. There are few observations on the spectrum of mixed proteinopathies in DS patients. Objective: This study aimed to evaluate multiple disease-associated proteinopathies in a series of DS cases. Methods: We analyzed the distribution of neurodegenerative disease associated proteins in postmortem brain samples from 11 DS cases (6 females, median age 57, range 38–66 years). Sections were stained for phosphorylated tau, 3-repeat and 4-repeat tau, amyloid-β, alpha synuclein, phosphorylated TDP-43, and p62. A comprehensive anatomical mapping and staging were applied for all proteins. …Results: Tau and amyloid-β pathology was prevalent in all cases and compatible with that typically seen in AD with some subtle deviations. Four of 11 cases presented with Lewy-related pathology (LRP). Two cases followed the Braak staging (stage 4 and 5) whereas 2 cases presented with an atypical distribution. Two cases showed limbic predominant age-related TDP-43 encephalopathy (LATE) (stage 1 and stage 2) neuropathologic change. Two cases exhibited aging-related tau astrogliopathy (ARTAG). Conclusion: In addition to subtle deviations from AD regarding the morphology of amyloid-β deposition and distribution of neuronal tau pathology, we find that the spectrum of mixed-pathologies in DS show distinctive features such as deviations from the Braak staging of LRP and that LATE neuropathologic change and ARTAG pathology can be seen in individuals younger than in sporadic AD cases. Our observations support the notion that DS has distinctive pathogenic pathways from sporadic AD. Show more

Keywords: Age-related tau astrogliopathy, alpha-synuclein, amyloid-β, cerebral amyloid angiopathy, Down syndrome, mixed pathology, tau, transactive response DNA binding protein 43 kDa

DOI: 10.3233/JAD-215675

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 595-607, 2022

Authors: Solomon, Victoria | Hafez, Madonna | Xian, Haotian | Harrington, Michael G. | Fonteh, Alfred | Yassine, Hussein N.

Article Type: Research Article

Abstract: Background: Mechanistic studies in animal models implicate a role for saturated fatty acids in neurodegeneration, but validation of this finding in human studies is still lacking. Objective: We investigated how cerebrospinal levels of sphingomyelins (SM) and phosphatidylcholine (PC)-containing saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids associate with total tau and phosphorylated tau (p-tau). Methods: Cerebrospinal fluid (CSF) lipids were measured in two cohorts, a discovery and a confirmation cohort of older non-demented individuals from the University of Southern California and Huntington Medical Research Institutes cohorts. Lipid analysis was performed using hydrophilic interaction liquid …chromatography, and individual PC and SM lipid species were measured using tandem mass spectrometry. In addition, CSF levels of Aβ42, total tau, and p-tau-181 were measured using an MSD multiplex assay. Results: The discovery cohort (n  = 47) consisted of older individuals and more females compared to the confirmation cohort (n  = 46). Notwithstanding the age and gender differences, and a higher p-tau, Aβ42 , and LDL-cholesterol in the discovery cohort, CSF concentrations of dipalmitoyl-PC (PC32a:0) were significantly associated with p-tau in both cohorts. Similarly, total saturated PC but not mono or polyunsaturated PCs correlated with p-tau concentrations in both cohorts. Conclusion: Saturated PC species in CSF associate with early markers of neurodegeneration and are potential early disease progression biomarkers. We propose mechanisms by which saturated PC may promote tau hyperphosphorylation. Show more

Keywords: Alzheimer’s disease biomarkers, cerebrospinal fluid, lipidomics, saturated fat, tau

DOI: 10.3233/JAD-215643

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 609-617, 2022

Authors: Yang, Changhao | Kang, Beipei | Cao, Zipeng | Zhang, Jianbin | Zhao, Fang | Wang, Diya | Su, Peng | Chen, Jingyuan

Article Type: Research Article

Abstract: Background: Early-life Pb exposure can cause behavioral and cognitive problems and induce symptoms of hyperactivity, impulsivity, and inattention in children. Studies showed that blood lead levels were highly correlated with neuropsychiatric disorders, and effects of neurotoxicity might persist and affect the incidence of neurodegenerative diseases, for example Alzheimer’s disease (AD). Objective: To explore possible mechanisms of developmental Pb-induced neuropsychiatric dysfunctions. Methods: Children were divided into low blood lead level (BLL) group (0–50.00μg/L) and high BLL group (> 50.00μg/L) and blood samples were collected. miRNA array was used to testify miRNA expression landscape between two groups. Correlation analysis …and real-time PCR were applied to find miRNAs that altered in Pb and neuropsychiatric diseases. Animal models and cell experiments were used to confirm the effect of miRNAs in response to Pb, and siRNA and luciferase experiments were conducted to examine their effect on neural functions. Results: miRNA array data and correlation analysis showed that miR-34b was the most relevant miRNA among Pb neurotoxicity and neuropsychiatric disorders, and synapse-associated membrane protein 2 (VAMP2) was the target gene regulating synapse function. In vivo and in vitro studies showed Pb exposure injured rats’ cognitive abilities and induced upregulation of miR-34b and downregulation of VAMP2, resulting in decreases of hippocampal synaptic vesicles. Blockage of miR-34b mitigated Pb’s effects on VAMP2 in vitro . Conclusion: Early-life Pb exposure might exert synapse-toxic effects via inhibiting VAMP2 mediated by upregulation of miR-34b and shed a light on the underlying relationship between Pb neurotoxicity and developmental neuropsychiatric disorders. Show more

Keywords: Lead, miRNA, neuropsychiatric disorders, synapse function

DOI: 10.3233/JAD-215638

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 619-633, 2022