Journal of Alzheimer's Disease - Volume 92, issue 4

Authors: Liu, Hanxiang | Reynolds, Gavin P. | Wei, Xianwen

Article Type: Research Article

Abstract: Background: Exposure to environmental neurotoxins associated with agricultural work, such as pesticides, may be a risk factor for neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s (PD) diseases. There is strong evidence that such exposure is associated with the development of PD; for AD the current evidence is equivocal. Several mechanisms are proposed to mediate this environmental toxicity, one of which is oxidative stress. Uric acid (UA) is an endogenous antioxidant, low levels of which are also implicated in neurodegenerative disease. Objective: This study aimed to determine whether agricultural work was a risk factor for AD in a …population in which its association with PD was established, and whether UA was also associated with AD in this cohort. Methods: Hospital records of subjects meeting criteria for AD (n  = 128) or vascular dementia (VaD) (n  = 178) after hospital admission for symptoms of dementia were studied. History of agricultural work and plasma UA were recorded and their relationship to diagnosis determined. Results: In contrast to previous findings in this population in which agricultural work was strongly associated with PD, a history of agricultural work was not over-represented in hospital admission for AD versus VaD. AD was associated with a reduced level of circulating UA compared with VaD. Conclusion: Agricultural work as a likely proxy for exposure to pesticides appears not to be a risk factor for AD to the extent found in PD, perhaps reflecting their differences in neuronal pathology. Nevertheless, findings with UA suggests that oxidative stress may be an important factor in AD pathogenesis. Show more

Keywords: Agricultural work, Alzheimer’s disease, pesticides, uric acid, neurodegeneration

DOI: 10.3233/JAD-221226

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1283-1287, 2023

Authors: Lazarova, Maria I. | Tancheva, Lyubka P. | Tasheva, Krasimira N. | Denev, Petko N. | Uzunova, Diamara N. | Stefanova, Miroslava O. | Tsvetanova, Elina R. | Georgieva, Almira P. | Kalfin, Reni E.

Article Type: Research Article

Abstract: Background: The neurodegenerative process in Alzheimer’s disease, one of the most common types of dementia worldwide, mostly affects the cholinergic neurotransmitter system and, to a lesser extent, the monoaminergic one. The antioxidant acetylcholinesterase (AChE) and triple monoamine reuptake inhibitory activity of Sideritis scardica (S. scardica) and other Sideritis species has already been reported. Objective: To investigate the effects of S. scardica water extracts on the learning and memory processes, anxiety-like behavior, and locomotor activities in scopolamine (Sco)-induced dementia in mice. Methods: Male Albino IRC mice were used. The plant extract was administered for …11 consecutive days in the presence or absence of Sco (1 mg/kg, i.p). The behavioural performance of the animals was evaluated by passive avoidance, T-maze, and hole-board tests. The effects of extract on AChE activity, brain noradrenalin (NA), and serotonin (Sero) content, and antioxidant status were also monitored. Results: Our experimental data revealed that the S. scardica water extract caused a reduction in degree of memory impairment and anxiety-like behaviour in mice with scopolamine-induced dementia. The extract did not affect changed by the Sco AChE activity but impact reduced brain NA and Sero levels and demonstrated moderate antioxidant activity. In healthy mice we did not confirm the presence of anxiolytic-like and AChE inhibitory effects of the S. scardica water extract. The extract did not change the control Sero brain levels and reduce those of NA. Conclusion: S. scardica water extract demonstrated memory preserving effect in mice with scopolamine-induced dementia and deserve further attention. Show more

Keywords: Anxiety, behaviour, cholinergic function, dementia, mice, monoaminergic function, scopolamine

DOI: 10.3233/JAD-230017

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1289-1302, 2023

Authors: García-Escobar, Greta | Puig-Pijoan, Albert | Puente-Periz, Víctor | Fernández-Lebrero, Aida | María Manero, Rosa | Navalpotro-Gómez, Irene | Suárez-Calvet, Marc | Grau-Rivera, Oriol | Contador-Muñana, José | Cascales-Lahoz, Diego | Duran-Jordà, Xavier | Boltes, Núncia | Pont-Sunyer, Maria Claustre | Ortiz-Gil, Jordi | Carrillo-Molina, Sara | López-Villegas, María Dolores | Abellán-Vidal, María Teresa | Martínez-Casamitjana, María Isabel | Hernández-Sánchez, Juan José | Padrós-Fluvià, Anna | Peña-Casanova, Jordi | Sánchez-Benavides, Gonzalo

Article Type: Research Article

Abstract: Background: Neuropsychological assessments are essential to define the cognitive profile and contribute to the diagnosis of Alzheimer’s disease (AD). The progress in knowledge about the pathophysiological process of the disease has allowed conceptualizing AD through biomarkers as a biological continuum that encompasses different clinical stages. Objective: To explore the association between cerebrospinal fluid (CSF) biomarkers of AD and cognition using the NEURONORMA battery, in a sample of cognitively unimpaired (CU), mild cognitive impaired (MCI), and mild dementia of the Alzheimer type (DAT) subjects, and to characterize the cognitive profiles in MCI subjects classified by A/T/N system. …Methods: 42 CU, 35 MCI, and 35 mild DAT were assessed using the NEURONORMA battery. Core AD biomarkers [amyloid-β42 (Aβ42 ) peptide, total tau (t-tau), and phosphorylated tau 181 (p-tau181)] proteins were measured in CSF. Correlation coefficients, multivariate regression, and effect sizes were calculated. We explored the age- and education-adjusted cognitive profiles by A/T/N variants within the MCI group. Results: Cognitive outcomes were directly associated with CSF Aβ42 and inversely with CSF tau measures. We found differences in both biomarkers and cognitive outcomes comparing all pairs except for CSF measures between cognitively impaired groups. The highest effect size was in memory tasks and biomarkers ratios. Lower performances were in memory and executive domains in MCI subjects with AD pathology (A+T+N±) compared to those with normal levels of AD biomarkers (A– T– N). Conclusion: This study provides further evidence of the validity of Spanish NEURONORMA cognitive battery to characterize cognitive impairment in the AD pathological continuum. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, cognitively unimpaired, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-220930

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1303-1321, 2023

Authors: Bukhbinder, Avram S. | Hinojosa, Miriam | Harris, Kristofer | Li, Xiaojin | Farrell, Christine M. | Shyer, Madison | Goodwin, Nathan | Anjum, Sahar | Hasan, Omar | Cooper, Susan | Sciba, Lois | Vargas, Amanda Falk | Hunter, David H. | Ortiz, Guadalupe J. | Chung, Karen | Cui, Licong | Zhang, Guo-Qiang | Fisher-Hoch, Susan P. | McCormick, Joseph B. | Schulz, Paul E.

Article Type: Research Article

Abstract: Background: Accurately identifying cognitive changes in Mexican American (MA) adults using the Mini-Mental State Examination (MMSE) requires knowledge of population-based norms for the MMSE, a scale which has widespread use in research settings. Objective: To describe the distribution of MMSE scores in a large cohort of MA adults, assess the impact of MMSE requirements on their clinical trial eligibility, and explore which factors are most strongly associated with their MMSE scores. Methods: Visits between 2004–2021 in the Cameron County Hispanic Cohort were analyzed. Eligible participants were ≥18 years old and of Mexican descent. MMSE distributions before …and after stratification by age and years of education (YOE) were assessed, as was the proportion of trial-aged (50–85– year-old) participants with MMSE <24, a minimum MMSE cutoff most frequently used in Alzheimer’s disease (AD) clinical trials. As a secondary analysis, random forest models were constructed to estimate the relative association of the MMSE with potentially relevant variables. Results: The mean age of the sample set (n  = 3,404) was 44.4 (SD, 16.0) years old and 64.5% female. Median MMSE was 28 (IQR, 28-29). The percentage of trial-aged participants (n  = 1,267) with MMSE <24 was 18.6% overall and 54.3% among the subset with 0–4 YOE (n  = 230). The five variables most associated with the MMSE in the study sample were education, age, exercise, C-reactive protein, and anxiety. Conclusion: The minimum MMSE cutoffs in most phase III prodromal-to-mild AD trials would exclude a significant proportion of trial-aged participants in this MA cohort, including over half of those with 0–4 YOE. Show more

Keywords: Cameron County Hispanic Cohort, clinical trial eligibility, Mexican Americans, Mini-Mental State Examination

DOI: 10.3233/JAD-220934

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1323-1339, 2023

Authors: Zhang, Feng | Niu, Long | Zhong, Rujia | Li, Song | Le, Weidong

Article Type: Research Article

Abstract: Background: Emerging evidence indicates that sleep disorders are the common non-cognitive symptoms of Alzheimer’s disease (AD), and they may contribute to the pathogenesis of this disease. Objective: In this study, we aim to investigate the effect of chronic sleep deprivation (CSD) on AD-related pathologies with a focus on tau phosphorylation and the underlying DNA methylation regulation. Methods: AβPPswe /PS1Δ E9 AD mice and their wild-type (WT) littermates were subjected to a two-month CSD followed by electroencephalography and electromyography recording. The mice were examined for learning and memory evaluation, then pathological, biochemical, and epigenetic assessments including …western blotting, immunofluorescence, dot blotting, and bisulfite sequencing. Results: The results show that CSD caused sleep disturbances shown as sleep pattern change, poor sleep maintenance, and increased sleep fragmentation. CSD increased tau phosphorylation at different sites and increased the level of tau kinases in AD and WT mice. The increased expression of cyclin-dependent kinase 5 (CDK5) may result from decreased DNA methylation of CpG sites in the promoter region of CDK5 gene, which might be associated with the downregulation of DNA methyltransferase 3A and 3B. Conclusion: CSD altered AD-related tau phosphorylation through epigenetic modification of tau kinase gene. The findings in this study may give insights into the mechanisms underlying the effects of sleep disturbances on AD pathology and provide new therapeutic targets for the treatment of this disease. Show more

Keywords: Alzheimer’s disease, DNA methylation, epigenetics, sleep disturbances, tau pathology

DOI: 10.3233/JAD-221048

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1341-1355, 2023

Authors: Xu, Shan | Xie, Linyun | Zhang, Yao | Wu, Xiao | Hong, Hui | Zhang, Ruiting | Zeng, Qingze | Li, Kaicheng | Luo, Xiao | Zhang, Minming | Sun, Jianzhong | Huang, Peiyu

Article Type: Research Article

Abstract: Background: The inferior frontal sulci are essential sites on the route of cerebrospinal fluid outflow. A recent study suggests that inferior frontal sulcal hyperintensities (IFSH) on FLAIR images might be related to glymphatic dysfunction. Objective: To investigate whether IFSH is associated with Alzheimer’s disease (AD) pathology and cerebral small vessel disease (SVD) burden. Methods: We retrospectively collected data from 272 non-demented subjects in the ADNI3 database. The IFSH was assessed on 3D fluid-attenuated inversion recovery images. The standardized uptake value ratios of amyloid and tau PET were used to reflect the AD pathology burden. To measure …the SVD burden, we assessed white matter hyperintensities (WMH), dilation of perivascular spaces, microbleeds, and lacunes. Finally, we performed ordinal logistic regression analyses to investigate the associations between the IFSH score and AD pathology and SVD burden. Results: The IFSH score was associated with the deep WMH score (OR, 1.79; 95% CI, 1.24 – 2.59) controlling for age and sex. The association remained significant in the multivariable regression models. There was no association between the IFSH score and AD pathology burden. Conclusion: This study suggests that the IFSH sign is associated with SVD but not AD pathology. Further studies are needed to confirm the findings. Show more

Keywords: Alzheimer’s disease, inferior frontal sulcal hyperintensity, magnetic resonance imaging, small vessel disease, white matter hyperintensities

DOI: 10.3233/JAD-220843

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1357-1365, 2023

Authors: Haddad, Seyyed M.H. | Pieruccini-Faria, Frederico | Montero-Odasso, Manuel | Bartha, Robert

Article Type: Research Article

Abstract: Background: Altered white matter (WM) tract integrity may contribute to mild cognitive impairment (MCI) and gait abnormalities. Objective: The purpose of this study was to determine whether diffusion tensor imaging (DTI) metrics were altered in specific portions of WM tracts in people with MCI and to determine whether gait speed variations were associated with the specific DTI metric changes. Methods: DTI was acquired in 44 people with MCI and 40 cognitively normal elderly controls (CNCs). Fractional anisotropy (FA) and radial diffusivity (RD) were measured along 18 major brain WM tracts using probabilistic tractography. The average FA …and RD along the tracts were compared between the groups using MANCOVA and post-hoc tests. The tracts with FA or RD differences between the groups were examined using an along-tract exploratory analysis to identify locations that differed between the groups. Associations between FA and RD in whole tracts and in the segments of the tracts that differed between the groups and usual/dual-task gait velocities and gross cognition were examined. Results: Lower FA and higher RD was observed in right cingulum-cingulate gyrus endings (rh.ccg) of the MCI group compared to the CNC group. These changes were localized to the posterior portions of the rh.ccg and correlated with gait velocities. Conclusion: Lower FA and higher RD in the posterior portion of the rh.ccg adjacent to the posterior cingulate suggests decreased microstructural integrity in the MCI group. The correlation of these metrics with gait velocities suggests an important role for this tract in maintaining normal cognitive-motor function. Show more

Keywords: Diffusion tensor imaging, mild cognitive impairment, single-task and dual-task gait, white matter tracts, whole-brain tractography

DOI: 10.3233/JAD-220476

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1367-1384, 2023

Authors: Bonomi, Chiara Giuseppina | Assogna, Martina | Di Donna, Martina Gaia | Bernocchi, Francesca | De Lucia, Vincenzo | Nuccetelli, Marzia | Fiorelli, Denise | Loizzo, Stefano | Mercuri, Nicola Biagio | Koch, Giacomo | Martorana, Alessandro | Motta, Caterina

Article Type: Research Article

Abstract: Background: Many transversal mechanisms act synergistically at different time-points in the cascade of Alzheimer’s disease (AD), since amyloid-β (Aβ) deposition, tau pathology, and neuroinflammation influence each other. Objective: We explored the contributions of microglia and astrocytes in patients with symptomatic sporadic AD stratified according to AT(N) system and APOE genotype. Methods: We compared the cerebrospinal fluid (CSF) levels of sTREM-2 and markers of astrocytic activation (GFAP; β-S100) from 71 patients with AD (23 A+T–,48 A+T+; 38 APOE ɛ 3, 33 APOE ɛ 4) and 30 healthy controls (HC). With multivariate analyses we investigated …associations between glial biomarkers, Aβ42 , and p-tau in all subgroups. Results: CSF sTREM-2 was higher in A+T+ [1.437 (0.264)] and A+T– [1.355 (0.213)] than in HC [1.042 (0.198); both p  < 0.001]; GFAP and β-S100 were comparable across groups. Considering all patients, sTREM-2 positively associated with Aβ42 (p  = 0.04) and p-tau (=0.016), with the first being present only in the A+T– subgroup (p  = 0.023). GFAP positively associated with Aβ42 in all patients (p  = 0.020) and in the A+T+ subgroup (p  = 0.04). Stratifying by APOE , a positive association of sTREM-2 and p-tau was confirmed selectively in carriers of ɛ 4 (p  = 0.018). Finally, sTREM-2 positively correlated with β-S100 in all subgroups, and with GFAP in A+T+ (p  = 0.042). Conclusion: Our results confirm the increase of CSF sTREM-2 in AD, which associates with reduced amyloidopathy in A+T– patients. Moreover, microglial activation seems to increase CSF tau levels in carriers of APOE ɛ 4, is associated with astrocytic reactivity (GFAP) in A+T+, and likely leads the acquisition of a more neurotoxic astrocytic phenotype (β-S100). Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease continuum, astrocytes, β-S100, biomarkers, GFAP, microglia, soluble TREM-2

DOI: 10.3233/JAD-221010

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1385-1397, 2023

Authors: Hollenbenders, Yasmin | Pobiruchin, Monika | Reichenbach, Alexandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder with homogenous disease patterns. Neuropathological changes precede symptoms by up to two decades making neuroimaging biomarkers a prime candidate for early diagnosis, prognosis, and patient stratification. Objective: The goal of the study was to discern intermediate AD stages and their precursors based on neuroanatomical features for stratifying patients on their progression through different stages. Methods: Data include grey matter features from 14 brain regions extracted from longitudinal structural MRI and cognitive data obtained from 1,017 healthy controls and AD patients of ADNI. AD progression was modeled with a …Hidden Markov Model, whose hidden states signify disease stages derived from the neuroanatomical data. To tie the progression in brain atrophy to a behavioral marker, we analyzed the ADAS-cog sub-scores in the stages. Results: The optimal model consists of eight states with differentiable neuroanatomical features, forming two routes crossing once at a very early point and merging at the final state. The cortical route is characterized by early and sustained atrophy in cortical regions. The limbic route is characterized by early decrease in limbic regions. Cognitive differences between the two routes are most noticeable in the memory domain with subjects from the limbic route experiencing stronger memory impairments. Conclusion: Our findings corroborate that more than one pattern of grey matter deterioration with several discernable stages can be identified in the progression of AD. These neuroanatomical subtypes are behaviorally meaningful and provide a door into early diagnosis of AD and prognosis of the disease’s progression. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, brain atrophy, clustering, hidden Markov model, longitudinal data, magnetic resonance imaging, patient stratification, subtype

DOI: 10.3233/JAD-221061

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1399-1412, 2023

Authors: He, Yan | Li, Junjie | Yi, Liling | Li, Xiaohuan | Luo, Man | Pang, Yayan | Wang, Maoju | Li, Zhaolun | Xu, Mingliang | Dong, Zhifang | Du, Yehong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β peptide (Aβ) deposition. Aβ accumulation induces oxidative stress, leading to mitochondrial dysfunction, apoptosis, and so forth. Octadecaneuropeptide (ODN), a diazepam-binding inhibitor (DBI)-derived peptide, has been reported to have antioxidant properties. However, it is unclear whether ODN has neuroprotective effects in AD. Objective: To profile the potential effects of ODN on AD. Methods: We established a mouse model of AD via microinjection of Aβ in the lateral ventricle. Utilizing a combination of western blotting assays, electrophysiological recordings, and behavioral tests, we investigated the neuroprotective effects of …ODN on AD. Results: DBI expression was decreased in AD model mice and cells. Meanwhile, ODN decreased Aβ generation by downregulating amyloidogenic AβPP processing in HEK-293 cells stably expressing human Swedish mutant APP695 and BACE1 (2EB2). Moreover, ODN could inhibit Aβ-induced oxidative stress in primary cultured cells and mice, as reflected by a dramatic increase in antioxidants and a decrease in pro-oxidants. We also found that ODN could reduce oxidative stress-induced apoptosis by restoring mitochondrial membrane potential, intracellular Ca2+ and cleaved caspase-3 levels in Aβ-treated primary cultured cells and mice. More importantly, intracerebroventricular injection of ODN attenuated cognitive impairments as well as long-term potentiation in Aβ-treated mice. Conclusion: These results suggest that ODN may exert a potent neuroprotective effect against Aβ-induced neurotoxicity and memory decline via its antioxidant effects, indicating that ODN may be a potential therapeutic agent for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognition, octadecaneuropeptide, oxidative stress

DOI: 10.3233/JAD-221115

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1413-1426, 2023