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

Authors: Hatada, Yutaka | Hashimoto, Mamoru | Shiraishi, Shinya | Ishikawa, Tomohisa | Fukuhara, Ryuji | Yuki, Seiji | Tanaka, Hibiki | Miyagawa, Yusuke | Kitajima, Mika | Uetani, Hiroyuki | Tsunoda, Naoko | Koyama, Asuka | Ikeda, Manabu

Article Type: Research Article

Abstract: Background: Although cerebral microbleeds (CMBs) are commonly observed in patients with Alzheimer’s disease (AD), their clinical relevance for AD remains unclear. Objective: We investigated the significance of CMBs in AD by examining the relationship between CMBs and cerebral blood flow (CBF) in patients with AD. Methods: Thirty-four patients (aged 77.9±7.6 years; 17 men) with probable AD and multiple (≥8) CMBs were selected from 394 consecutive patients. For each lobe of the brain, the correlation between the number of CMBs observed on susceptibility-weighted images and the decrease in CBF observed on single-photon emission computed tomography was assessed. …Results: The number of microbleeds was significantly correlated with the severity of decrease in the occipital lobe (Spearman’s r  = 0.531, p  < 0.001) and temporal lobe (r  = 0.437, p  < 0.001) but not in the frontal lobe (r  = 0.201, p  = 0.101) and parietal lobe (r  = 0.178, p  = 0.146). These results were unchanged in the partial correlational analysis after controlling the effect of other small vessel disease such as lacunars and white matter hyperintensities. Conclusion: Multiple CMBs are associated with cerebral hypoperfusion in AD. The effects of CMBs on CBF differed according to brain location, possibly reflecting different distributions of the underlying cerebral amyloid angiopathy and AD-related histopathology, such as neurofibrillary tangles. Show more

Keywords: Alzheimer’s disease, amyloid angiopathy, cerebral blood flow, cerebral microbleeds

DOI: 10.3233/JAD-190272

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 273-280, 2019

Authors: Osborn, Katie E. | Alverio, Jonathan M. | Dumitrescu, Logan | Pechman, Kimberly R. | Alzheimer’s Disease Neuroimaging Initiative | Gifford, Katherine A. | Hohman, Timothy J. | Blennow, Kaj | Zetterberg, Henrik | Jefferson, Angela L.

Article Type: Research Article

Abstract: Background: Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer’s disease pathology influences the brain’s vulnerability in this regard is not well understood. Objective: Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer’s disease. Methods: Among Alzheimer’s Disease Neuroimaging Initiative participants with normal cognition (n  = 117), mild cognitive impairment (n  = 190), and Alzheimer’s disease (n  = 95), linear regression related vascular risk (as …measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of Aβ42 , hyperphosphorylated tau, and total tau. Results: Vascular risk and neurofilament light were not related in the main effect model (p  = 0.08). However, interactions emerged for total tau (p  = 0.01) and hyperphosphorylated tau (p  = 0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer’s disease biomarker profiles (p  = 0.046) where in comparison to the referent ‘normal’ biomarker group, individuals with abnormal levels of both Aβ42 and total tau showed stronger associations between vascular risk and neurofilament light. Conclusion: Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer’s disease pathology. Show more

Keywords: Alzheimer’s disease, cerebrovascular, neurodegeneration, neurofilament light, vascular risk

DOI: 10.3233/JAD-190077

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 281-290, 2019

Authors: Wu, Beibei | Wang, Yujing | Shi, Chenggang | Chen, Yao | Yu, Lexiang | Li, Juan | Li, Weiwei | Wei, Yan | He, Rongqiao

Article Type: Research Article

Abstract: Advanced glycation end products (AGEs) have been implicated in the disease process of diabetes mellitus. They have also been found in senile plaques and neurofibrillary tangles in the brains of Alzheimer’s disease patients. Furthermore, abnormally high levels of D-ribose and D-glucose were found in the urine of patients with type 2 diabetes mellitus, suggesting that diabetic patients suffer from dysmetabolism of not only D-glucose but also D-ribose. In the present study, intravenous tail injections of ribosylated rat serum albumin (RRSA) were found to impair memory in rats, but they did not markedly impair learning, as measured by the Morris water …maze test. Injections of RRSA were found to trigger tau hyperphosphorylation in the rat hippocampus via GSK-3β activation. Tau hyperphosphorylation and GSK-3β activation were also observed in N2a cells in the presence of ribosylation-derived AGEs. Furthermore, the administration of ribosylation-derived AGEs induced the suppression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB). Both GSK-3β inhibition and BDNF treatment decreased the levels of phosphorylated tau in N2a cells. In particular, the administration of BDNF could rescue memory failure in ribosylated AGE-injected rats. Ribosylation-derived AGEs downregulated the BDNF-TrkB pathway in rat brains and N2a cells, leading to GSK-3β activation-mediated tau hyperphosphorylation, which was involved in the observed rat memory loss. Targeting ribosylation may be a promising therapeutic strategy to prevent Alzheimer’s disease and diabetic encephalopathies. Show more

Keywords: Advanced glycation end products, brain-derived neurotrophic factor, GSK-3β oxidative stress, ribosylation, tau hyperphosphorylation

DOI: 10.3233/JAD-190158

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 291-305, 2019

Authors: Lennon, Matthew J. | Makkar, Steve R. | Crawford, John D. | Sachdev, Perminder S.

Article Type: Research Article

Abstract: Background: Hypertension is an established risk factor for stroke and vascular dementia but recent meta-analyses examining the association between Alzheimer’s disease (AD) and hypertension have found no significant association. These meta-analyses included short term studies starting in late life which may have obscured the real effect of midlife hypertension. Objective: To examine the association of AD with midlife hypertension, by including only studies with a sufficiently long follow up duration. Methods: Relevant studies were found by searches of MEDLINE, EMBASE, and PubMed. Study outcomes were grouped by measures of blood pressure and definition of hypertension (e.g., …systolic hypertension > 140 mmHg or > 160 mmHg). We assessed pooled effect estimates using random effects models and heterogeneity of pooled estimates through the I2 statistic. Results: Literature search found 3,426 publications of which 7 were eligible studies. There was a significant association between systolic hypertension (>160 mm Hg) and AD (HR 1.25, 95CI 1.06 – 1.47, p  = 0.0065). Similarly, for systolic hypertension > 140 mm Hg, there was a smaller but still significant association (HR 1.18, 95CI 1.02 – 1.35, p  = 0.021). For diastolic hypertension, all four studies found no significant associations between diastolic hypertension and AD, and these data could not be pooled due to heterogeneity in reporting. Conclusions: Our study found that midlife stage 1 and stage 2 systolic hypertension is associated with increased risk of AD by 18 and 25%, respectively, although no association was found for diastolic hypertension. It is likely that assertive control of systolic hypertension starting in midlife is important to preventing AD. Show more

Keywords: Alzheimer’s disease, dementia, hypertension, meta-analysis, midlife

DOI: 10.3233/JAD-190474

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 307-316, 2019

Authors: Kleipool, Emma E.F. | Trappenburg, Marijke C. | Rhodius-Meester, Hannke F.M. | Lemstra, Afina W. | van der Flier, Wiesje M. | Peters, Mike J.L. | Muller, Majon

Article Type: Research Article

Abstract: Background: Orthostatic hypotension (OH) has been cross-sectionally and longitudinally related to dementia in the general population. Whether OH contributes to clinical progression to mild cognitive impairment (MCI) or dementia is less certain. Also, differences in risk of progression between patients with early OH (EOH) versus delayed and/or prolonged OH (DPOH) are unclear. Objective: Assess the prevalence of EOH and DPOH, investigate the longitudinal association between EOH and DPOH and either incident MCI or dementia. Methods: 1,882 patients from the Amsterdam Dementia Cohort [64±8 years; 43% female; n  = 500 with subjective cognitive decline (SCD), n  = 341 MCI, …n  = 758 Alzheimer’s disease (AD), n  = 49 vascular dementia (VaD), n  = 146 frontotemporal dementia (FTD), n  = 88 Lewy body dementia (DLB)]. Definition OH: systolic blood pressure (BP) drop≥20 mmHg and/or a diastolic BP drop≥10 mmHg at 1 and/or 3 minutes after standing. EOH: OH only at 1 minute, DPOH: OH at (1 and) 3 minutes. Results: Prevalence OH: 19% SCD, 28% MCI, 41% dementia. Compared to SCD, odds of having OH were highest in patients with VaD and DLB; ORs (95% CI) were 2.6 (1.4–4.7) and 5.1 (3.1–8.4), respectively. After a mean (SD) follow-up of 2.2 (1.4) years, 105 (22%) of SCD or MCI patients showed clinical progression. Compared to patients without OH, those with DPOH had an increased risk of progression; hazard ratio (95% CI) was 1.7 (1.1–2.7), and those with EOH did not; 0.8 (0.3–1.9). Conclusion: Compared to SCD, prevalence of OH was higher in MCI and highest in dementia, particularly in VaD and DLB. DPOH, more likely associated with autonomic dysfunction, is a risk factor for incident MCI or dementia. Show more

Keywords: Blood pressure, clinical progression, dementia, orthostatic hypotension

DOI: 10.3233/JAD-190402

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 317-325, 2019

Authors: Feng, Tian | Yamashita, Toru | Shang, Jingwei | Shi, Xiaowen | Nakano, Yumiko | Morihara, Ryuta | Tsunoda, Keiichiro | Nomura, Emi | Sasaki, Ryo | Tadokoro, Koh | Matsumoto, Namiko | Hishikawa, Nozomi | Ohta, Yasuyuki | Abe, Koji

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect …of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis. Show more

Keywords: Alzheimer’s disease, chronic cerebral hypoperfusion, edaravone, neural oxidative stress, neuronal loss, neuroinflammation

DOI: 10.3233/JAD-190369

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 327-339, 2019

Authors: Wong, Mark Yu Zheng | Tan, Chuen Seng | Venketasubramanian, Narayanaswamy | Chen, Christopher | Ikram, M.K. | Cheng, Ching-Yu | Hilal, Saima

Article Type: Research Article

Abstract: Background: Dementia is the leading cause of dependency and disability among older persons worldwide. There remains, however, limited studies on dementia rates within the Asia-Pacific region, with little data on differences across major Asian ethnic groups. Objective: To study the prevalence of cognitive impairment (CI) and dementia in community-dwelling Indians from Singapore and to examine interethnic differences among Chinese, Malays, and Indians. Methods: Participants (>60 years) drawn from the Indian component of the multiethnic Epidemiology of Dementia in Singapore (EDIS) study were screened using the locally validated Abbreviated Mental Test and Progressive Forgetfulness Questionnaire. Screen-positive participants …underwent further detailed neuropsychological assessments. CI was classified into Cognitive impairment no dementia (CIND)-mild, CIND-moderate, and dementia. Results: Of 961 Indian adults, 120 (12.5%) had CIND-mild, 101 (10.5%) CIND-moderate, and 12 (1.2%) dementia. The overall age-standardized prevalence of any CI was 24.6%. The prevalence of any CI increased with age (15.7% in ages 60–64 years to 30.1% in ages≥80 years), and was higher in women than men. Multivariate analysis showed that age, lower education, and hypertension were independently associated with CI. Even after demographic and cardiovascular risk factor adjustment, Indians were more likely to be cognitively impaired compared to Chinese (odds ratio [OR], 95% CI:1.37 [1.01–1.86 ]) but not Malays (0.89 [0.72–1.10]). Conclusions: Among elderly Indians, the overall prevalence of any CI was 24.6%. Despite similar assessment protocols and risk factor adjustments, the prevalence of CI was higher in Indians compared to Chinese but similar to Malays. Further research is needed to unravel other factors that may underlie these ethnic differences. Show more

Keywords: Cognitive impairment, dementia, epidemiology, Indian, prevalence, population-based, risk factors

DOI: 10.3233/JAD-190610

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 341-351, 2019

Authors: Kostev, Karel | Bohlken, Jens | Jacob, Louis

Article Type: Research Article

Abstract: Background: Most previous studies focusing on the migraine headache-dementia relationship have failed to simultaneously adjust for several common comorbidities. Objective: The goal of this retrospective cohort study was to investigate the association between migraine headaches and dementia in general practices in the UK. Methods: The current study sample included patients who received a migraine diagnosis in one of 67 general practices in the UK between January 1997 and December 2016 (index date). Patients without migraine diagnoses were matched 1 : 1 to patients with migraine diagnoses based on propensity scores using a greedy algorithm and derived from the …logistic regression using age, sex, index year, and co-diagnoses. The main outcome of the study was the association between migraine headaches and the incidence of dementia within 10 years of the index date. Results: This study included 7,454 individuals with or without migraine diagnoses. Mean age was 67.7 years (SD = 5.8 years), and 72.9% of patients were women. Within 10 years of the index date, 5.2% of participants with and 3.7% of those without migraine headaches were diagnosed with dementia (log-rank p  < 0.001). The respective figures were 5.8% and 3.6% in women (log-rank p  < 0.001) and 4.5% and 3.4% in men (log-rank p  = 0.722). We observed a positive association between migraine diagnoses and all-cause dementia (hazard ratio [HR] = 1.43) as well as Alzheimer’s disease (HR = 1.87). Sensitivity analyses further revealed that these associations were only significant in women (all-cause dementia: HR = 1.65; Alzheimer’s disease: HR = 2.27). Conclusion: Migraine diagnoses were positively associated with all-cause dementia and Alzheimer’s disease in women. Show more

Keywords: Dementia, migraine, retrospective cohort study, sex differences, United Kingdom

DOI: 10.3233/JAD-190581

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 353-360, 2019