Journal of Alzheimer's Disease - Volume 41, issue 3

Authors: Cadena-del-Castillo, Carla | Valdes-Quezada, Christian | Carmona-Aldana, Francisco | Arias, Clorinda | Bermúdez-Rattoni, Federico | Recillas-Targa, Félix

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a complex disorder whose etiology is associated with environmental and genetic factors. Recently there have been several attempts to analyze the role of epigenetic alterations in the origin and progression of this neurodegenerative condition. To evaluate the potential participation of the methylation status of the genome that may contribute to AD progression, we have studied the levels and distribution of the 5-methylcytosine and 5-hydroxymethylcytosine in different brain regions at different ages. We analyzed and quantified the immunosignal of these two epigenetic marks in young versus old wild-type mice and in the triple-transgenic mouse model of AD …(3xTg-AD). The results show a decline in global 5-methylcytosine mark over time in all studied brain regions concomitant with a significant and widespread increase in 5-hydroxymethylcytosine mark in the aged transgenic mice in contrast to the age-matched controls. These differences in the methylation pattern of brain DNA in the 3xTg-AD that accumulates along age indicates abnormal formation of permissive chromatin structure associated with the increase in AD-related markers. Show more

Keywords: Aging, Alzheimer's disease, chromatin, DNA methylation, 5-hydroxymethylcytosine, 3xTg-AD

DOI: 10.3233/JAD-132285

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 845-854, 2014

Authors: Shih, Yao-Hsiang | Tsai, Kuen-Jer | Lee, Chu-Wan | Shiesh, Shu-Chu | Chen, Wei-Ting | Pai, Ming-Chyi | Kuo, Yu-Min

Article Type: Research Article

Abstract: It has been demonstrated that peripheral injection of anti-amyloid-β (Aβ) antibodies to patients with Alzheimer's disease (AD) and AD transgenic mice facilitate Aβ clearance. We hypothesized that peripheral circulating Aβ-binding proteins also possess the ability to enhance Aβ clearance and the levels of circulating Aβ-binding proteins could serve as early AD biomarkers. Circulating Aβ-binding proteins were isolated from plasma and identified by LC-MS/MS. Their levels were compared among non-demented individuals without AD family history (ND), with AD family history (ND-FH), and patients with mild AD. The results showed that most of the identified Aβ-binding proteins were apolipoproteins, i.e., apoA-I, apoB-100, …apoC-III, and apoE. Aβ bound preferentially to apoA-I-enriched HDL, followed by apoC-III- and apoE-enriched VLDL, and bound less favorably to apoB-100-enriched LDL. Levels of apoA-I were reduced in AD patients and could be used to discriminate AD from ND groups (AUC: 0.93); whereas levels of apoC-III were reduced in both ND-FH and AD groups and could be used to differentiate ND-FH from ND individuals (AUC: 0.81). Both the levels of apoA-1 and apoC-III positively correlated with CASI and MMSE scores. In conclusion, these results suggest that plasma apoA-I could be a sensitive AD biomarker and individuals with low plasma levels of apoC-III are at risk for AD. Show more

Keywords: Amyloid-β binding protein, apolipoprotein, biomarker, family history, plasma

DOI: 10.3233/JAD-140111

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 855-865, 2014

Authors: Green, Christopher J. | Holly, Jeffrey M.P. | Bayer, Antony | Fish, Mark | Ebrahim, Shah | Gallacher, John | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: Background: The increasing incidence of cognitive impairment and dementia in an aging population poses a significant burden on healthcare. Consequently, identifying modifiable physiological factors which may influence the onset of cognitive decline are becoming increasingly important. Previous studies have suggested an association between levels of insulin-like growth factors and cognitive function. Objective: To investigate whether low IGF-I, IGF-II, and IGF molar ratio is associated with greater cognitive decline and increased risk of dementia. Methods: We examined prospective associations between IGF-I, IGF-II, and IGFBP-3 and cognitive function in the Caerphilly Prospective Study (CaPS) (n = 746 men) …from samples obtained around 1986, with assessment in around 2003 for clinical diagnosis of cognitive impairment but no dementia (CIND) or dementia, as well as with CAMCOG scores at three phases. Results: A one standard deviation increase in IGF-II was associated with a reduced odds ratio for CIND (0.76, 95% CI 0.60, 0.96) which hardly altered after further adjustment for confounders. A one standard deviation increase in IGFBP-3 among participants without dementia or CIND was associated with greater decline in cognition (p = 0.002) equivalent to 2.4 years difference in age. All the associations between IGF-I and our outcomes were consistent with chance. Conclusion: In this study of men, we found that both IGF-II and IGFBP-3 are associated with normal age-related cognitive decline and clinical pathology associated with CIND, but we failed to replicate previous associations with IGF-I. Assuming these findings are replicated, they may provide new insights into potential biological mechanisms that underlie age-related cognitive changes and development of dementia. Show more

Keywords: Dementia, insulin-like growth factors, mild cognitive impairment, prospective cohort study

DOI: 10.3233/JAD-132183

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 867-875, 2014

Authors: Sun, Qiying | Hampel, Harald | Blennow, Kaj | Lista, Simone | Levey, Allan | Tang, Beisha | Li, Rena | Shen, Yong

Article Type: Research Article

Abstract: Evidence suggests that the tumor necrosis factor receptor (TNFR)-signaling pathway contributes to the pathogenesis of Alzheimer's disease (AD). TNF-α converting enzyme (TACE/ADAM-17) can cleave both pro-TNF-α and TNF receptors. Recently, we have shown that TACE activity in the cerebrospinal fluid (CSF) of subjects with mild cognitive impairment (MCI) and AD patients is significantly higher than that of cognitively healthy controls (HC). To date, it is not clear whether TACE activity could be detected in the human plasma and whether TACE activity in MCI and AD patients is different from that in HC. We analyzed TACE expression and activity in a …large clinical sample of 64 patients with AD, 88 subjects with MCI, and 50 age-matched HC recruited from two distinct academic centers. Plasma TACE protein levels did not differ significantly in the three study groups (AD, MCI, and HC). However, plasma TACE activity in subjects with MCI and AD patients was significantly higher than that in HC. Moreover, in MCI and AD groups, we found a significant correlation between plasma TACE activity and CSF t-tau and Aβ42 levels and CSF Aβ42 /tau ratios. In AD patients, the levels of plasma TACE activity correlated significantly and negatively with cognition. These findings further support the role of the TNF-α receptor complex in AD-related neuroinflammation and propose TACE plasma activity as a promising hypothesis-driven biomarker candidate for detection, diagnosis, and prognosis of prodromal and clinical AD. Show more

Keywords: Alzheimer's disease, biomarker, mild cognitive impairment, plasma, tumor necrosis factor converting enzyme

DOI: 10.3233/JAD-140177

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 877-886, 2014

Authors: Sánchez-Benavides, Gonzalo | Peña-Casanova, Jordi | Casals-Coll, Marta | Gramunt, Nina | Molinuevo, José L. | Gómez-Ansón, Beatriz | Aguilar, Miguel | Robles, Alfredo | Antúnez, Carmen | Martínez-Parra, Carlos | Frank-García, Anna | Fernández-Martínez, Manuel | Blesa, Rafael | for the NEURONORMA Study Team

Article Type: Research Article

Abstract: The aim of this study was to characterize the neuropsychological and neuroimaging profiles of mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients, and to study the magnitude of the differences by comparing both outcomes with healthy subjects in a cross-sectional manner. Five hundred and thirty-five subjects (356 cognitively normal adults (CONT), 79 MCI, and 100 AD) were assessed with the NEURONORMA neuropsychological battery. Thirty CONT, 23 MCI, and 23 AD subjects from this sample were included in the neuroimaging substudy. Patients' raw cognitive scores were converted to age and education-adjusted scaled ones (range 2–18) using co-normed reference values. Medians …were plotted to examine the cognitive profile. MRIs were processed by means of FreeSurfer. Effect size indices (Cohen's d) were calculated in order to compare the standardized differences between patients and healthy subjects. Graphically, the observed cognitive profiles for MCI and AD groups produced near to parallel lines. Verbal and visual memories were the most impaired domains in both groups, followed by executive functions and linguistic/semantic ones. The largest effect size between AD and cognitively normal subjects was found for the FCSRT (d = 4.05, AD versus CONT), which doubled the value obtained by the best MRI measure, the right hippocampus (d = 1.65, AD versus CONT). Our results support the notion of a continuum in cognitive profile between MCI and AD. Neuropsychological outcomes, in particular the FCSRT, are better than neuroimaging ones at detecting differences among subjects. Show more

Keywords: Alzheimer's disease, magnetic resonance imaging, mild cognitive impairment, neuropsychological tests, neuropsychology

DOI: 10.3233/JAD-132186

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 887-901, 2014

Authors: Struyfs, Hanne | Molinuevo, José L. | Martin, Jean-Jacques | De Deyn, Peter Paul | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: The cerebrospinal fluid (CSF) biomarkers amyloid-β peptide of 42 amino acids (Aβ1-42 ), total tau-protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P ) are used to diagnose Alzheimer's disease (AD). In order to increase diagnostic power, several biomarker combinations have been proposed. In that sense, a new CSF biomarker index was developed, the AD-CSF-index, which has been validated in clinically diagnosed AD patients using electrochemoluminescence based Meso Scale Discovery and single-analyte ELISA kits. This study validated the AD-CSF-index in neuropathologically diagnosed AD patients, using both single-analyte ELISA and multi-analyte Luminex assays. CSF of 51 neuropathologically diagnosed AD patients and …of 95 controls was analyzed by commercially available single-analyte ELISA-kits (INNOTEST® , Innogenetics) and by a Research Use Only version of the multi-analyte Luminex xMAP® assay (INNO-BIA AlzBio3, Innogenetics). Subsequently the AD-CSF-indices were calculated. Both T-tau and P-tau181P AD-CSF-indices were significantly increased in AD patients when compared to controls (p < 0.001). The diagnostic power of the indices was calculated using ROC analyses, resulting in excellent sensitivity and specificity values that systematically exceeded the 80% threshold for discriminating autopsy-confirmed AD patients from controls, independent of the analytical platform. The power to discriminate between AD and non-AD dementias was not included in this study and should be validated in the future. In conclusion, this study validated the AD-CSF-index in autopsy-confirmed AD patients and has shown that its excellent diagnostic accuracy is independent of the analytical platform. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, diagnostic accuracy, sensitivity, specificity

DOI: 10.3233/JAD-131085

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 903-909, 2014

Authors: Campanari, Maria-Letizia | García-Ayllón, María-Salud | Belbin, Olivia | Galcerán, Joan | Lleó, Alberto | Sáez-Valero, Javier

Article Type: Research Article

Abstract: The cholinergic enzyme acetylcholinesterase (AChE) and the catalytic component of the γ-secretase complex, presenilin-1 (PS1), are known to interact. In this study, we investigate the consequences of AChE-PS1 interactions, particularly the influence of AChE in PS1 levels and γ-secretase activity. PS1 is able to co-immunoprecipitate all AChE variants (AChE-R and AChE-T) and molecular forms (tetramers and light subunits) present in the human brain. Overexpression of AChE-R or AChE-T, or their respective inactive mutants, all trigger an increase in PS1 protein levels. The AChE species capable of triggering the biggest increase in PS1 levels is a complex of AChE with the …membrane anchoring subunit proline-rich membrane anchor (PRiMA), which restricts the localization of the resulting AChE tetramer to the outer plasma membrane. Incubation of cultured cells with soluble AChE demonstrates that AChE is able to increase PS1 at both the protein and transcript levels. However, the increase of PS1 caused by soluble AChE is accompanied by a decrease in γ-secretase activity as shown by the reduction of the processing of the amyloid-β protein precursor. This inhibitory effect of AChE on γ-secretase activity was also demonstrated by directly assessing accumulation of CTF-AβPP in cell-free membrane preparations incubated with AChE. Our data suggest that AChE may function as an inhibitor of γ-secretase activity. Show more

Keywords: Acetylcholinesterase, Alzheimer's disease, γ-secretase, inhibitor, presenilin 1

DOI: 10.3233/JAD-140426

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 911-924, 2014

Authors: Zhou, Xiaoqing | Zhang, Junying | Chen, Yaojing | Ma, Tao | Wang, Yunxia | Wang, Jun | Zhang, Zhanjun

Article Type: Research Article

Abstract: Type 2 diabetes mellitus is a metabolic disorder and a risk factor for dementia and mild cognitive impairment (MCI), which could also increase the risk of progression from MCI to dementia. The present study evaluated the spontaneous neuronal activity of 31 patients with MCI using resting-state functional MRI. The patients were divided into two groups (17 MCI patients without diabetes, and 14 patients with type 2 diabetes who were considered as the MCI-DM group) and 17 well-matched healthy controls were also recruited. The amplitude of low-frequency fluctuations (ALFF) of spontaneous blood oxygen level dependent signals was then applied to assess …neuroimaging changes. To further investigate the impact of type 2 diabetes on cognition, the correlation of ALFF and the neuropsychological tests for the MCI-DM and MCI group were calculated. MCI-DM patients showed diffused ALFF changes in a variety of brain regions that were significantly related to cognitive performance, including the frontal lobe, the temporal lobe, the hippocampus, the amygdala, and the precuneus during a resting state; whereas, the alterations were much less pronounced in the MCI patients without diabetes. These findings provide new insights into understanding essential of diabetes mellitus and may help to clarify the relationship between diabetes mellitus and dementia. Show more

Keywords: Functional MRI, mild cognitive impairment, resting-state, spontaneous brain activity, type 2 diabetes

DOI: 10.3233/JAD-132354

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 925-935, 2014

Authors: Brandt, Jason | Blehar, Justin | Anderson, Allan | Gross, Alden L.

Article Type: Research Article

Abstract: Most approaches to the detection of presymptomatic or prodromal Alzheimer's disease require the costly collection and analysis of biological samples or neuroimaging measurements. The Dementia Risk Assessment (DRA) was developed to facilitate this detection by collecting self-report and proxy-report of dementia risk variables and episodic memory performance on a free Internet website. We now report two validation studies. In Study 1, 130 community-residing older adults seeking memory screening at senior health fairs were tested using the Mini-Cog, and were then observed while taking the DRA. They were compared to a demographically-matched subsample from our anonymous Internet sample. Participants seeking memory …screening had more dementia risk factors and obtained lower scores on the DRA's recognition memory test (RMT) than their Internet controls. In addition, those who failed the Mini-Cog obtained much lower scores on the RMT than those who passed the Mini-Cog. In Study 2, 160 older adults seeking evaluation of cognitive difficulties took the DRA prior to diagnostic evaluations at outpatient dementia clinics. Patients who ultimately received the diagnosis of a dementia syndrome scored significantly lower on the RMT than those diagnosed with other conditions or deemed normal. Lower education, family history of dementia, presence of hypercholesterolemia and diabetes, and memory test score distinguished the dementia and no-dementia groups with around 82% accuracy. In addition, score on the RMT correlated highly with scores on other instruments widely used to detect cognitive decline. These findings support the concurrent validity of the DRA for detecting prevalent cognitive impairment. Prospective studies of cognitively normal persons who subsequently develop dementia will be necessary to establish its predictive validity. Show more

Keywords: Memory testing, neuropsychology, risk factors, screening

DOI: 10.3233/JAD-140297

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 937-945, 2014

Authors: Dourado, Marcia C.N. | Mograbi, Daniel C. | Santos, Raquel L. | Sousa, Maria Fernanda B. | Nogueira, Marcela L. | Belfort, Tatiana | Landeira-Fernandez, Jesus | Laks, Jerson

Article Type: Research Article

Abstract: Despite the growing understanding of the conceptual complexity of awareness, there currently exists no instrument for assessing different domains of awareness in dementia. In the current study, the psychometric properties of a multidimensional awareness scale, the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia (ASPIDD), are explored in a sample of 201 people with dementia and their family caregivers. Cronbach's alpha was high (α = 0.87), indicating excellent internal consistency. The mean of corrected item-total correlation coefficients was moderate. ASPIDD presented a four-factor solution with a well-defined structure: awareness of activities of daily living, cognitive functioning and health …condition, emotional state, and social functioning and relationships. Functional disability was positively correlated with total ASPIDD, unawareness of activities of daily living, cognitive functioning, and with emotional state. Caregiver burden was correlated with total ASPIDD scores and unawareness of cognitive functioning. The results suggest that ASPIDD is indeed a multidimensional scale, providing a reliable measure of awareness of disease in dementia. Further studies should explore the risk factors associated with different dimensions of awareness in dementia. Show more

Keywords: Alzheimer's disease, anosognosia, awareness of disease, dementia, factor analysis

DOI: 10.3233/JAD-140183

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 947-956, 2014