Journal of Alzheimer's Disease - Volume 65, issue 4

Authors: Parra-Anguita, Laura | Moreno-Cámara, Sara | López-Franco, María Dolores | Pancorbo-Hidalgo, Pedro L.

Article Type: Research Article

Abstract: Background: There are currently no questionnaires to measure the knowledge of nurses about dementia or Alzheimer’s disease care in the Spanish language. Objective: To validate the Spanish version of the Dementia Knowledge Assessment Tool 2 (DKAT2-Sp). Methods: The DKAT2 was translated into Spanish and then back-translated. The new Spanish version was validated in a sample of 361 members of the nursing staff from 24 nursing homes and a sample of 297 nursing students in Spain. Psychometric properties were assessed through an item analysis, a Rasch analysis, differential item functioning analysis, construct validity (known groups), and internal …consistency (Cronbach’s alpha). Results: The 21 items of the DKAT2-Sp fit the model well, showing a wide range of difficulty. Four items have differential items functioning between nursing professionals and students. The DKAT2-Sp shows acceptable internal consistency (Cronbach’s alpha = 0.76 for nursing professionals and 0.83 for students). Scores obtained in the known groups test were as hypothesized (Nursing home staff mean = 15.57 versus Nursing student mean = 12.85; p  < 0.0001 for mean difference), supporting construct validity. Conclusion: The DKAT2-Sp is a reliable and valid questionnaire to measure knowledge about dementia in both nursing professionals and nursing students in Spanish-speaking contexts. Show more

Keywords: Alzheimer’s disease, dementia, knowledge, nursing care, validation

DOI: 10.3233/JAD-180290

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1175-1183, 2018

Authors: Rodríguez-Cruz, Fanny | Torres-Cruz, Francisco Miguel | Monroy-Ramírez, Hugo Christian | Escobar-Herrera, Jaime | Basurto-Islas, Gustavo | Avila, Jesús | García-Sierra, Francisco

Article Type: Research Article

Abstract: Abnormal fibrillary aggregation of tau protein is a pathological condition observed in Alzheimer’s disease and other tauopathies; however, the presence and pathological significance of early non-fibrillary aggregates of tau remain under investigation. In cell and animal models expressing normal or modified tau, toxic effects altering the structure and function of several membranous organelles have also been reported in the absence of fibrillary structures; however, how these abnormalities are produced is an issue yet to be addressed. In order to obtain more insights into the mechanisms by which tau may disturb intracellular membranous elements, we transiently overexpressed human full-length tau and …several truncated tau variants in cultured neuroblastoma cells. After 48 h of transfection, either full-length or truncated tau forms produced significant fragmentation of the Golgi apparatus (GA) with no changes in cell viability. Noteworthy is that in the majority of cells exhibiting dispersion of the GA, a ring-shaped array of cortical or perinuclear microtubule (Mt) bundles was also generated under the expression of either variant of tau. In contrast, Taxol treatment of non-transfected cells increased the amount of Mt bundles but not sufficiently to produce fragmentation of the GA. Tau-induced ring-shaped Mt bundles appeared to be well-organized and stable structures because they were resistant to Nocodazole post-treatment and displayed a high level of tubulin acetylation. These results further indicate that a mechanical force generated by tau-induced Mt-bundling may be responsible for Golgi fragmentation and that the repeated domain region of tau may be the main promoter of this effect. Show more

Keywords: Alzheimer’s disease, confocal microscopy, Golgi apparatus, immunofluorescence, microtubule lattice, tau

DOI: 10.3233/JAD-180547

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1185-1207, 2018

Authors: Holden, John G. | Cosnard, Alexandre | Laurens, Brice | Asselineau, Julien | Biotti, Damien | Cubizolle, Stéphanie | Dupouy, Sandrine | Formaglio, Maıté | Koric, Lejla | Seassau, Magali | Tilikete, Caroline | Vighetto, Alain | Tison, François

Article Type: Research Article

Abstract: Saccade alterations are potential early signs of Alzheimer’s disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer’s disease (n  = 29), as compared to both aged-matched mild Alzheimer’s disease patients (n  = 23) and controls (n  = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p … < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer’s disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer’s disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p  = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer’s disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer’s disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, executive function, saccadic eye movements

DOI: 10.3233/JAD-180082

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1209-1223, 2018

Authors: Campbell, Jared M. | Stephenson, Matthew D. | de Courten, Barbora | Chapman, Ian | Bellman, Susan M. | Aromataris, Edoardo

Article Type: Research Article

Abstract: Background: Metformin, a first line antihyperglycemic medication, is an AMPK activator and has been hypothesized to act as a geroprotective agent. Studies on its association with various classifications of age-related cognitive decline have shown mixed results with positive and negative findings. Objective: To synthesize the best available evidence on the association of metformin-use with risk, progression, and severity of dementia. Method: Eligible research investigated the effect of metformin on dementia, Alzheimer’s disease, or any measure of cognitive impairment compared to any control group who were not receiving metformin. The initial search resulted in 862 citations from …which 14 studies (seven cohort, four cross-sectional, two RCTs, and one case control) were included. Results: Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88). Mini-Mental State Examination scores were not significantly affected by metformin-use, although both RCTs showed that metformin had a neuroprotective effect compared to placebo. Some studies found negative or neutral effects for metformin use by people with diabetes; the potential mechanism of metformin-induced vitamin B12 deficiency is discussed. Conclusions: Metformin should continue to be used as a first line therapy for diabetes in patients at risk of developing dementia or Alzheimer’s disease. The use of metformin by individuals without diabetes for the prevention of dementia is not supported by the available evidence. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, diabetes mellitus, meta-analysis, metformin, systematic review

DOI: 10.3233/JAD-180263

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1225-1236, 2018

Authors: Lee, Jin San | Kim, Seonwoo | Yoo, Heejin | Park, Seongbeom | Jang, Young Kyoung | Kim, Hee Jin | Kim, Ko Woon | Kim, Yeshin | Jang, Hyemin | Park, Key-Chung | Yaffe, Kristine | Yang, Jin-Ju | Lee, Jong-Min | Na, Duk L. | Seo, Sang Won

Article Type: Research Article

Abstract: Background/Objective: In this study, we investigated a long-term trajectory of brain aging (from the 20 s to over-80) in cognitively normal (CN) individuals. We further determined whether differences in sex, education years, and apolipoprotein E ε 4 status affect age-related cortical thinning. Methods: A total of 2,944 CN individuals who underwent high-resolution (3.0-Tesla) magnetic resonance imaging were included in this study. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age-related cortical thinning and related factors. Results: Compared to those in their 20 s/30 s, participants in their …40 s showed thinning primarily in the medial and lateral frontal and inferior parietal regions, and cortical thinning occurred across most of the cortices with increasing age. Notably, the precuneus, inferior temporal and lateral occipital regions were relatively spared until later in life. Male and lower education years were associated with greater cortical thinning with distinct regional specificity. Conclusion: Our findings provide an important clue to understanding the mechanism of age-related cognitive decline and new strategies for preventing the acceleration of pathological brain aging. Show more

Keywords: Alzheimer’s disease, cognitive disorders, dementia, magnetic resonance imaging

DOI: 10.3233/JAD-170537

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1237-1246, 2018

Authors: Javanshiri, Keivan | Waldö, Maria Landqvist | Friberg, Niklas | Sjövall, Fredrik | Wickerström, Karin | Haglund, Mattias | Englund, Elisabet

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most prevalent cause of dementia with vascular dementia (VaD) being second alongside with mixed AD and VaD, according to some. For some time, it has been proposed that cardiovascular disease (CaVD), hypertension, and diabetes mellitus (DM), which are known risk factors for VaD, also are associated with and contribute to the development of AD. Objective: The aim of this study was to investigate the prevalence of these proposed general risk factors, and to document presence of CaVD as evidenced from clinical records or from autopsy findings, further to correlate these with the …diagnoses AD, VaD and mixed AD-VaD (MD), respectively. Methods: Autopsy reports at the Clinical Department of Pathology in Lund from 1992–2017 were analyzed. All cases with a complete autopsy report and a neuropathologically diagnosed dementia disorder (AD, VaD, or MD) were selected on the condition of a clinical diagnosis of dementia. Clinical data were retrieved through medical records and the Swedish National Diabetes Register (NDR). A total of 268 subjects were included. Results: In AD, there was less CaVD as significantly less organ/tissue findings (p < 0.05), significantly less hypertension (p < 0.001), and likewise significantly less DM (p = 0.0014) than in VaD, with the MD group results being set between these two in all aspects studied. Conclusion: AD and VaD exhibit such different profiles of organ and vascular damage as well as of hypertension and DM that they clearly point toward different pathogenic origin with low likelihood of shared risk factors. Show more

Keywords: Alzheimer’s disease, autopsy, cardiovascular disease, dementia, dementia vascular, diabetes mellitus, hypertension, risk factors

DOI: 10.3233/JAD-180644

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1247-1258, 2018

Authors: Yuan, Hongjuan | Yang, Wenjie

Article Type: Research Article

Abstract: To evaluate whether genetically increased serum uric acid levels influence the risk of Alzheimer’s disease (AD), we used genome-wide significant single nucleotide polymorphisms for uric acid as the instrumental variables, and undertook a Mendelian randomization (MR) study to estimate the effect of uric acid on the risk of AD. The MR method prevents bias due to reverse causation (e.g., uric acid changes because of AD) and minimizes bias due to confounding of both measured and unmeasured confounders. We used the summary statistics from The International Genomics of Alzheimer’s Project Consortium that is the largest AD genome-wide association study of 74,046 …individuals of European ethnicity including 25,580 AD cases. We further performed sensitivity analyses to evaluate the assumptions of the MR method. The MR analyses did not support a causal role of genetically elevated serum uric acid on AD risk (odds ratio: 1.02, 95% confidence interval: 0.93–1.12, p  = 0.65). Sensitivity analyses, including MR-Egger regression, suggested no strong evidence of bias due to pleiotropy. In conclusion, lifelong genetically increased serum uric acid levels have no protective effect on the risk of AD. Show more

Keywords: Alzheimer’s disease, genetic correlation, Mendelian randomization, uric acid

DOI: 10.3233/JAD-180538

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1259-1265, 2018

Authors: Yumoto, Sakae | Kakimi, Shigeo | Ishikawa, Akira

Article Type: Research Article

Abstract: Increasing evidence indicates that metal-induced oxidative stress plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). Recently, the presence of 8-hydroxydeoxyguanosine, a biomarker of oxidative DNA damage, was demonstrated in nuclear DNA (nDNA) in the AD brain. Iron (Fe) is a pro-oxidant metal capable of generating hydroxyl radicals that can oxidize DNA, and aluminum (Al) has been reported to facilitate Fe-mediated oxidation. In the present study, we examined the elements contained in the nuclei of nerve cells in AD brains using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS). Our results demonstrated that Al and Fe were …colocalized in the nuclei of nerve cells in the AD brain. Within the nuclei, the highest levels of both Al and Fe were measured in the nucleolus. The SEM-EDS analysis also revealed the colocalization of Al and Fe in the heterochromatin and euchromatin in neuronal nuclei in the AD brain. Notably, the levels of Al and Fe in the nucleus of nerve cells in the AD brain were markedly higher than those in age-matched control brains. We hypothesize that the colocalization of Al and Fe in the nucleus of nerve cells might induce oxidative damage to nDNA and concurrently inhibit the repair of oxidatively damaged nDNA. An imbalance caused by the increase in DNA damage and the decrease in DNA repair activities might lead to the accumulation of unrepaired damaged DNA, eventually causing neurodegeneration and the development of AD. Show more

Keywords: Aluminum, Alzheimer’s disease, DNA damage, electron microscopy, energy-dispersive X-ray spectroscopy, iron, Fenton reaction, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-171108

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1267-1281, 2018

Authors: de Oliveira, Fabricio Ferreira | de Almeida, Sandro Soares | Chen, Elizabeth Suchi | Smith, Marilia Cardoso | Naffah-Mazzacoratti, Maria da Graça | Bertolucci, Paulo Henrique Ferreira

Article Type: Research Article

Abstract: Lifetime risk factors for cognitive and functional decline in Alzheimer’s disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated …systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, educational status, neurodegenerative diseases, neuropsychiatry, risk factors

DOI: 10.3233/JAD-180303

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1283-1299, 2018

Authors: Buss, Stephanie S. | Padmanabhan, Jaya | Saxena, Sadhvi | Pascual-Leone, Alvaro | Fried, Peter J.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and type 2 diabetes (T2DM) are common causes of cognitive decline among older adults and share strong epidemiological links. Distinct patterns of cortical atrophy are observed in AD and T2DM, but robust comparisons between structure-function relationships across these two disease states are lacking. Objective: To compare how atrophy within distributed brain networks is related to cognition across the spectrum of cognitive aging. Methods: The relationship between structural MRI changes and cognition was studied in 22 mild-to-moderate AD, 28 T2DM, and 27 healthy participants. Cortical thickness measurements were obtained from networks of interest …(NOIs) matching the limbic, default, and frontoparietal resting-state networks. Composite cognitive scores capturing domains of global cognition, memory, and executive function were created. Associations between cognitive scores and the NOIs were assessed using linear regression, with age as a covariate. Within-network General Linear Model (GLM) analysis was run in Freesurfer 6.0 to visualize differences in patterns of cortical atrophy related to cognitive function in each group. A secondary analysis examined hemispheric differences in each group. Results: Across all groups, cortical atrophy within the limbic NOI was significantly correlated with Global Cognition (p = 0.009) and Memory Composite (p = 0.002). Within-network GLM analysis and hemispheric analysis revealed qualitatively different patterns of atrophy contributing to cognitive dysfunction between AD and T2DM. Conclusion: Brain network atrophy is related to cognitive function across AD, T2DM, and healthy participants. Differences in cortical atrophy patterns were seen between AD and T2DM, highlighting neuropathological differences. Show more

Keywords: Alzheimer’s disease, cognitive aging, dementia, diabetes mellitus, executive function, memory disorders

DOI: 10.3233/JAD-180570

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1301-1312, 2018