Journal of Alzheimer's Disease - Volume 71, issue 1

Authors: Dong, Yue | Brewer, Gregory J.

Article Type: Research Article

Abstract: Age and Alzheimer’s disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites …from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD+ /NADH-dependent redox sites, where age- and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid β -oxidation and glutamine. Overall age- and AD-related changes were > 2-fold when comparing the declines of upstream metabolites of NAD+ /NADH-dependent reactions to the increases of downstream metabolites (p  = 10-5 , n  = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1-phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning- and memory-related deficits. The data support the novel hypothesis that age- and AD-associated metabolic shifts respond to NAD(P)+ /NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity. Show more

Keywords: Alzheimer’s disease, aging, citric acid cycle, dehydrogenase, energy metabolism, fatty acids, glycolysis, hippocampus, NAD, oxidation-reduction

DOI: 10.3233/JAD-190408

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 119-140, 2019

Authors: Zonneveld, Hazel I. | Roshchupkin, Gennady V. | Adams, Hieab H.H. | Gutman, Boris A. | van der Lugt, Aad | Niessen, Wiro J. | Vernooij, Meike W. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: It is increasingly recognized that the complex functions of human cognition are not accurately represented by arbitrarily-defined anatomical brain regions. Given the considerable functional specialization within such regions, more fine-grained studies of brain structure could capture such localized associations. However, such analyses/studies in a large community-dwelling population are lacking. Objective: To perform a fine-mapping of cognitive ability to cortical and subcortical grey matter on magnetic resonance imaging (MRI). Methods: In 3,813 stroke-free and non-demented persons from the Rotterdam Study (mean age 69.1 (±8.8) years; 55.8% women) with cognitive assessments and brain MRI, we performed voxel-based …morphometry and subcortical shape analysis on global cognition and separate tests that tapped into memory, information processing speed, fine motor speed, and executive function domains. Results: We found that the different cognitive tests significantly associated with grey matter density in differential but also overlapping brain regions, primarily in the left hemisphere. Clusters of significantly associated voxels with global cognition were located within multiple anatomic regions: left amygdala, hippocampus, parietal lobule, superior temporal gyrus, insula and posterior temporal lobe. Subcortical shape analysis revealed associations primarily within the head and tail of the caudate nucleus, putamen, ventral part of the thalamus, and nucleus accumbens, more equally distributed among the left and right hemisphere. Within the caudate nucleus both positive (head) as well as negative (tail) associations were observed with global cognition. Conclusions: In a large population-based sample, we mapped cognitive performance to cortical and subcortical grey matter density using a hypothesis-free approach with high-dimensional neuroimaging. Leveraging the power of our large sample size, we confirmed well-known associations as well as identified novel brain regions related to cognition. Show more

Keywords: Aging, brain, cognition, epidemiology, gray matter, magnetic resonance imaging

DOI: 10.3233/JAD-181297

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 141-152, 2019

Authors: Martínez de Toda, Irene | Miguélez, Lara | Vida, Carmen | Carro, Eva | De la Fuente, Mónica

Article Type: Research Article

Abstract: Oxidative stress plays an essential and early role in the pathophysiology of Alzheimer’s disease (AD). Alterations in the redox state in AD and in mild cognitive impairment (MCI) patients appear in the brain and at peripheral level. Given that it is easier to study the latter, most of the research has been focused on plasma. However, the analysis of redox parameters in whole blood cells (including erythrocytes and leukocytes) has not really been investigated. Moreover, the association of these parameters with Mini-Mental State Examination (MMSE) clinical scores, has scarcely been studied. Therefore, the aim of the present work was to …analyze several redox markers in whole blood cells from male and female MCI and AD patients. Antioxidant (superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and reductase (GR) activities, and reduced glutathione (GSH) concentration) together with oxidant parameters (oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS)) were investigated using MCI and AD (10 women and 10 men in each group) and their age-matched control groups (15 women and 15 men). The results show an altered redox state in whole blood cells from AD patients (higher CAT, GSSG/GSH, TBARS and lower GPx, GR, GSH). Some of these redox parameters are already affected in MCI patients (higher TBARS and lower GPx and GR activities) in both sexes and, consequently, they could be used as markers of prodromal AD. Since GR, GSH, GSSG, and GSSG/GSH were found to be associated with MMSE scores, they seem to be useful clinically to monitor cognitive decline in AD progression. Show more

Keywords: Antioxidants, cognitive dysfunction, neurodegenerative diseases, oxidants, oxidative stress, preclinical markers

DOI: 10.3233/JAD-190198

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 153-163, 2019

Authors: Tustison, Nicholas J. | Holbrook, Andrew J. | Avants, Brian B. | Roberts, Jared M. | Cook, Philip A. | Reagh, Zachariah M. | Duda, Jeffrey T. | Stone, James R. | Gillen, Daniel L. | Yassa, Michael A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract:  Longitudinal studies of development and disease in the human brain have motivated the acquisition of large neuroimaging data sets and the concomitant development of robust methodological and statistical tools for quantifying neurostructural changes. Longitudinal-specific strategies for acquisition and processing have potentially significant benefits including more consistent estimates of intra-subject measurements while retaining predictive power. Using the first phase of the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1) data, comprising over 600 subjects with multiple time points from baseline to 36 months, we evaluate the utility of longitudinal FreeSurfer and Advanced Normalization Tools (ANTs) surrogate thickness values in the context of a linear …mixed-effects (LME) modeling strategy. Specifically, we estimate the residual variability and between-subject variability associated with each processing stream as it is known from the statistical literature that minimizing the former while simultaneously maximizing the latter leads to greater scientific interpretability in terms of tighter confidence intervals in calculated mean trends, smaller prediction intervals, and narrower confidence intervals for determining cross-sectional effects. This strategy is evaluated over the entire cortex, as defined by the Desikan-Killiany-Tourville labeling protocol, where comparisons are made with the cross-sectional and longitudinal FreeSurfer processing streams. Subsequent linear mixed effects modeling for identifying diagnostic groupings within the ADNI cohort is provided as supporting evidence for the utility of the proposed ANTs longitudinal framework which provides unbiased structural neuroimage processing and competitive to superior power for longitudinal structural change detection. Show more

Keywords: Advanced normalization tools, FreeSurfer, linear mixed effects models, longitudinal processing

DOI: 10.3233/JAD-190283

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 165-183, 2019

Authors: He, Hao | Xu, Pengfei | Wu, Tingting | Chen, Yiqi | Wang, Jing | Qiu, Yuehong | Fan, Jin | Guan, Qing | Luo, Yuejia

Article Type: Research Article

Abstract: Cognitive control for the coordination of mental operations is essential in normal cognitive functioning of daily life. Although the decline of cognitive control in older adults with mild cognitive impairment (MCI) has been demonstrated, whether this decline is a core deficit in MCI remains unclear. In this study, we employed a perceptual decision-making task to estimate the capacity of cognitive control (CCC) in older adults with MCI (n  = 55) and the age-, sex-, and education-matched healthy controls (HC, n  = 55) selected based on a commonly used battery of ten neuropsychological tests in five cognitive domains. We found that the CCC …was significantly correlated to the neuropsychological measures of the battery. The mean CCC was significantly lower in the MCI group (3.06 bps) than in the HC group (3.59 bps) and significantly lower in the amnestic MCI subgroup (2.90 bps) than in the nonamnestic MCI subgroup (3.22 bps). In detecting and classifying MCI using machine learning, the classifier with the CCC as the input feature outperformed the overall classification with neuropsychological measures in a single cognitive domain. The classification performance was significantly increased when the CCC was included as a feature in addition to measures in a single domain, and the CCC served as a key feature in optimal classifiers with inputs from multiple domains. These results support the hypothesis that the decline in cognitive control is a core deficit in MCI and suggest that the CCC may serve as a key index in the diagnosis of MCI. Show more

Keywords: Cognitive control, classification, executive function, machine learning, mild cognitive impairment

DOI: 10.3233/JAD-181006

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 185-200, 2019

Authors: Hack, Erica E. | Dubin, Joel A. | Fernandes, Myra A. | Costa, Sanduni M. | Tyas, Suzanne L.

Article Type: Research Article

Abstract: Background: Multilingualism is associated with enhanced executive function and may thus prevent cognitive decline and reduce the risk of dementia. Objective: To determine whether multilingualism is associated with delayed onset or reduced risk of dementia. Methods: Dementia was diagnosed in the Nun Study, a longitudinal study of religious sisters aged 75+ years. Multilingualism was self-reported. Dementia likelihood was determined in 325 participants using discrete-time survival analysis; sensitivity analyses (n  = 106) incorporated additional linguistic measures (idea density and grammatical complexity). Results: Multilingualism did not delay the onset of dementia. However, participants speaking four or more …languages (but not two or three) were significantly less likely to develop dementia than monolinguals (OR = 0.13; 95% CI = 0.01, 0.65, adjusted for age, apolipoprotein E, and transition period). This significant protective effect of speaking four or more languages weakened (OR = 0.53; 95% CI = 0.06, 4.91) in the presence of idea density in models adjusted for education and apolipoprotein E. Conclusion: Linguistic ability broadly was a significant predictor of dementia, although it was written linguistic ability (specifically idea density) rather than multilingualism that was the strongest predictor. The impact of language on dementia may extend beyond number of languages spoken to encompass other indicators of linguistic ability. Further research to identify the characteristics of multilingualism most salient for risk of dementia could clarify the value, target audience, and design of interventions to promote multilingualism and other linguistic training as a strategy to reduce the risk of dementia and its individual and societal impacts. Show more

Keywords: Cognitive reserve, cohort studies, dementia, epidemiology, language, multilingualism, risk, survival analysis

DOI: 10.3233/JAD-181302

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 201-212, 2019

Authors: Deibel, Scott H. | Young, Bryant | Mohajerani, Majid H. | McDonald, Robert J.

Article Type: Research Article

Abstract: Circadian rhythm dysfunction is present in Alzheimer’s disease. Animal models of Alzheimer’s disease have been employed to investigate whether this dysfunction is a risk factor or symptom of the disease. The circadian phenotype in mouse models of Alzheimer’s disease is very disparate in terms of the degree and timing of the dysfunction. This is likely a result of some models elevating amyloid-β protein precursor instead of just the amyloid-β fragment present in human Alzheimer’s disease. We characterized activity rhythms in a novel knock-in mouse model (APPNL-G-F ) of Alzheimer’s disease that elevates amyloid-β without overexpressing amyloid-β protein precursor. Despite increased …rhythm amplitude, total activity, and a shortening of free-running period at 15 months of age, all other aspects of the activity rhythm were similar to controls from three to fifteen months of age. At two months of age, these mice were also able to entrain to a light-dark cycle with a period right on the edge of entrainment, which further suggests a healthy functioning circadian system. These data open the possibility that circadian rhythm disruptions in transgenic models of Alzheimer’s disease could be a result of these models having an artificial phenotype caused by overexpression of amyloid-β protein precursor. Show more

Keywords: Alzheimer’s disease, APPNL-G-F mice, circadian rhythms, knock in, mouse models, transgenic

DOI: 10.3233/JAD-190102

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 213-225, 2019

Authors: Lacour, Morgane | Quenez, Olivier | Rovelet-Lecrux, Anne | Salomon, Bruno | Rousseau, Stephane | Richard, Anne-Claire | Quillard-Muraine, Muriel | Pasquier, Florence | Rollin-Sillaire, Adeline | Martinaud, Olivier | Zarea, Aline | de la Sayette, Vincent | Boutoleau-Bretonniere, Claire | Etcharry-Bouyx, Frédérique | Chauviré, Valérie | Sarazin, Marie | le Ber, Isabelle | Epelbaum, Stéphane | Jonveaux, Thérèse | Rouaud, Olivier | Ceccaldi, Mathieu | Godefroy, Olivier | Formaglio, Maite | Croisile, Bernard | Auriacombe, Sophie | Magnin, Eloi | Sauvée, Mathilde | Marelli, Cecilia | Gabelle, Audrey | Pariente, Jeremie | Paquet, Claire | Boland, Anne | Deleuze, Jean-François | Campion, Dominique | Hannequin, Didier | Nicolas, Gael | Wallon, David | The collaborators of the CNR-MAJ

Article Type: Research Article

Abstract: Background: Pathogenic variants in the autosomal dominant genes PSEN1 , PSEN2 , or APP , APOE4 alleles, and rare variants within TREM2 , SORL1 , and ABCA7 contribute to early-onset Alzheimer’s disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. Objective: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods: We first screened PSEN1 , PSEN2 , and APP in 154 EOAD patients with an onset before 51 years and a negative …family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2 , SORL1 , and ABCA7 . Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1 , 4 TREM2 , and 9 ABCA7. MC presented an earlier disease onset (p  < 0.0001) and associated neurologic symptoms more frequently (p  < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. Conclusion: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages. Show more

DOI: 10.3233/JAD-190193

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 227-243, 2019

Authors: Werden, Emilio | Khlif, Mohamed Salah | Bird, Laura J. | Cumming, Toby | Bradshaw, Jennifer | Khan, Wasim | Pase, Matthew | Restrepo, Carolina | Veldsman, Michele | Egorova, Natalia | Patel, Sheila K. | Gottlieb, Elie | Brodtmann, Amy

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) gene ɛ 4 allele is a risk factor for Alzheimer’s disease and cardiovascular disease. However, its relationship with cognition and brain volume after stroke is not clear. Objective: We compared cognition and medial temporal lobe volumes in APOE ɛ 4 carriers and non-carriers in the first year after ischemic stroke. Methods: We sampled 20 APOE ɛ 4 carriers and 20 non-carriers from a larger cohort of 135 ischemic stroke participants in the longitudinal CANVAS study. Participants were matched on a range of demographic and stroke characteristics. We used …linear mixed-effect models to compare cognitive domain z-scores (attention, processing speed, executive function, verbal and visual memory, language, visuospatial function) and regional medial temporal lobe volumes (hippocampal, entorhinal cortex) between groups at each time-point (3, 12-months post-stroke), and within groups across time-points. APOE gene single nucleotide polymorphisms (SNPs; rs7412, rs429358) were genotyped on venous blood. Results: APOE ɛ 4 carriers and non-carriers did not differ on any demographic, clinical, or stroke variable. Carriers performed worse than non-carriers in verbal memory at 3 months post-stroke (p  = 0.046), but were better in executive function at 12 months (p  = 0.035). Carriers demonstrated a significant improvement in verbal memory (p  = 0.012) and executive function (p  = 0.015) between time-points. Non-carriers demonstrated a significant improvement in visual memory (p  = 0.0005). Carriers had smaller bilateral entorhinal cortex volumes (p  < 0.05), and larger right sided and contralesional hippocampal volumes, at both time-points (p  < 0.05). Conclusion: APOE ɛ4 is associated with delayed recovery of verbal memory function and reduced entorhinal cortex volumes in the first year after ischemic stroke. Show more

Keywords: Apolipoproteins E, hippocampus, magnetic resonance imaging, memory, stroke

DOI: 10.3233/JAD-190566

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 245-259, 2019

Authors: Takenoshita, Naoto | Shimizu, Soichiro | Kanetaka, Hidekazu | Sakurai, Hirofumi | Suzuki, Ryo | Miwa, Takashi | Odawara, Masato | Ishii, Kenji | Shimada, Hitoshi | Higuchi, Makoto | Suhara, Tetsuya | Hanyu, Haruo

Article Type: Research Article

Abstract: Background/Objective: Although type 2 diabetes mellitus (DM) is a risk factor for the development of dementia, the underlying brain pathologies and mechanisms vary among patients. In this study, we classified patients with clinically diagnosed Alzheimer’s disease (AD) associated with DM into subgroups based on their amyloid and tau accumulation patterns on positron emission tomography (PET), and analyzed the differences in clinical features and brain imaging findings between the subgroups. Methods: Sixty-four patients with probable or possible AD associated with DM were classified using PiB (detects amyloid, A) and PBB3 (detects tau, T) PET studies. Patients were classified into …the A+/T+ group (n  = 35, AD pathology), the A– /T+ group (n  = 19, tauopathy), and the A– /T– group (n  = 10, non-amyloid/non-tau neuronal damage). Results: Compared with the A+/T+ group, the A– /T+ group showed less-well controlled glycemia, longer duration of diabetes, more glucose variability, higher frequency of insulin therapy and biochemical hypoglycemia, and greater impairment of frontal lobe function, slower progression of cognitive decline, fewer APOE4 carriers, less severe medial temporal lobe atrophy, and lower frequency of posterior cerebral hypoperfusion. This subgroup showed different clinical and radiological features from AD. Conclusion: Among patients with clinically diagnosed AD with DM, there are subgroups with neuronal damage independent of AD pathology. A subgroup of dementia patients suspected of having tauopathy is strongly associated with DM-related metabolic abnormalities. This study highlights the identification of a novel dementia subgroup (diabetes-related dementia), which is important for considering appropriate therapies and care in clinical practice. Show more

Keywords: Alzheimer’s disease, amyloid, diabetes mellitus, diabetes-related dementia, positron emission tomography, tau

DOI: 10.3233/JAD-190620

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 261-271, 2019