Journal of Alzheimer's Disease - Volume 33, issue 2

Authors: Gabelle, Audrey | Richard, Florence | Gutierrez, Laure-Anne | Schraen, Susanna | Delva, Fleur | Rouaud, Olivier | Buée, Luc | Dartigues, Jean-François | Touchon, Jacques | Lambert, Jean-Charles | Berr, Claudine

Article Type: Research Article

Abstract: Studies of plasma amyloid-β (Aβ) levels as potential biomarkers for incident Alzheimer's disease (AD) have yielded contradictory results. We explored the associations between plasma Aβ40 , Aβ42 , and truncated Aβ levels, and prognosis of dementia in participants of the prospective 3-City Study. 120 aged individuals diagnosed with 2-year incident dementia were followed up for seven years. The associations between Aβ plasma levels and baseline cognitive score, cognitive decline, and death were examined. A higher level of baseline plasma Aβ was associated with worse cognitive status two years prior to incident dementia diagnosis. In incident AD patients, the association was …only significant for Aβ40 and Aβn-42 . In the fast cognitive decliners group, especially in AD cases, a higher level of 5 pg/ml of baseline Aβ42 , Aβn-42 , Aβn-42 /Aβn-40 , and Aβ42 /Aβ40 ratios were associated with a lower risk of fast cognitive decline based on the Isaacs Set Test score. There was no association between peptide levels and mortality in demented subjects. When assayed at prodromal stage, plasma Aβ levels may be potentially useful markers of fast cognitive decline in individuals who subsequently become demented. Show more

Keywords: Alzheimer's disease, cohort studies, mild cognitive impairment, plasma amyloid-β peptides

DOI: 10.3233/JAD-2012-121147

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 381-391, 2013

Authors: Lewis, John E. | McDaniel, H. Reginald | Agronin, Marc E. | Loewenstein, David A. | Riveros, Jorge | Mestre, Rafael | Martinez, Mairelys | Colina, Niurka | Abreu, Dahlia | Konefal, Janet | Woolger, Judi M. | Ali, Karriem H.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a leading killer of Americans, imparts a significant toll on the quality of life of the patient and primary caregiver, and results in inordinate costs in an already overburdened medical system. Prior studies on cholinesterase inhibitors among AD patients have shown minimal amelioration of disease symptoms and/or restoration of lost cognitive functioning. The effect of improved nutrition, particularly with dietary supplements, on cognitive functioning may offer an alternative strategy compared to standard treatment. The present pilot study investigated the effect of an aloe polymannose multinutrient complex (APMC) formula on cognitive and immune functioning over 12 months …among adults diagnosed with AD. Subjects participated in an open-label trial and consumed 4 teaspoons per day of the APMC. The ADAS-cog, MMSE, ADCS-ADL, and SIB were administered at baseline and 3, 6, 9, and 12 months follow-up. Cytokines and lymphocyte and monocyte subsets were assessed at baseline and 12 months. The mean ADAS-cog cognition score significantly improved at 9 and 12 months from baseline, and 46% of our sample showed clinically-significant improvement (≥4-point change) from baseline to 12 months. Participants showed significant decreases in tumor necrosis factor-α, vascular endothelial growth factor, and interleukins-2 and-4. CD90+, CD95+CD3+, CD95+CD34+, CD95+CD90+, CD14+CD34+, CD14+CD90+, and CD14+CD95+ decreased significantly, whereas CD14+ significantly increased. Participants tolerated the APMC supplement with few, temporary adverse reactions. Our results showed improvements in both clinical and physiological outcomes for a disease that otherwise has no standard ameliorative remedy. Show more

Keywords: Aloe, Alzheimer disease, B-lymphocyte subsets, cognition, cytokines, dietary supplementation, growth factors, oligosaccharides, T-cell subsets

DOI: 10.3233/JAD-2012-121381

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 393-406, 2013

Authors: Hebda-Bauer, Elaine K. | Simmons, Tracy A. | Sugg, Andrew | Ural, Eren | Stewart, James A. | Beals, James L. | Wei, Qiang | Watson, Stanley J. | Akil, Huda

Article Type: Research Article

Abstract: Activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in response to the organism's innate need for homeostasis. The glucocorticoids (GCs) that are released into the circulation upon acute activation of the HPA axis perform stress-adaptive functions and provide negative feedback to turn off the HPA axis, but can be detrimental when in excess. Long-term activation of the HPA axis (such as with chronic stress) enhances susceptibility to neuronal dysfunction and death, and increases vulnerability to Alzheimer's disease (AD). However, little is known how components of the HPA axis, upstream of GCs, impact vulnerability to AD. This study examined basal gene expression …of stress-related molecules in brains of 3xTg-AD mice during early-stage pathology. Basal GC levels and mRNA expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and corticotropic releasing hormone (CRH) in several stress- and emotionality-related brain regions were measured in 3–4-month-old 3xTg-AD mice. Despite normal GC levels, young 3xTg-AD mice exhibit an activated central HPA axis, with altered mRNA levels of MR and GR in the hippocampus, GR and CRH in the paraventricular nucleus of the hypothalamus, GR and CRH in the central nucleus of the amygdala, and CRH in the bed nucleus of the stria terminalis. This HPA axis activation is present during early-stage neuropathology when 3xTg-AD mice show mild behavioral changes, suggesting an ongoing neuroendocrine regulation that precedes the onset of severe AD-like pathology and behavioral deficits. Show more

Keywords: Alzheimer's disease, corticotropic releasing hormone, glucocorticoid receptor, HPA axis, mineralocorticoid receptor, stress

DOI: 10.3233/JAD-2012-121438

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 407-422, 2013

Authors: Davenward, Samantha | Bentham, Peter | Wright, Jan | Crome, Peter | Job, Deborah | Polwart, Anthony | Exley, Christopher

Article Type: Research Article

Abstract: There has been a plausible link between human exposure to aluminum and Alzheimer's disease for several decades. We contend that the only direct and ethically acceptable experimental test of the ‘aluminum hypothesis’, which would provide unequivocal data specific to the link, is to test the null hypothesis that a reduction in the body burden of aluminum to its lowest practical limit would have no influence upon the incidence, progression, or severity of Alzheimer's disease. Herein we are testing the hypothesis that silicon-rich mineral waters can be used as non-invasive methods to reduce the body burden of aluminum in individuals with …Alzheimer's disease and a control group consisting of their carers and partners. We have shown that drinking up to 1 L of a silicon-rich mineral water each day for 12 weeks facilitated the removal of aluminum via the urine in both patient and control groups without any concomitant affect upon the urinary excretion of the essential metals, iron and copper. We have provided preliminary evidence that over 12 weeks of silicon-rich mineral water therapy the body burden of aluminum fell in individuals with Alzheimer's disease and, concomitantly, cognitive performance showed clinically relevant improvements in at least 3 out of 15 individuals. This is a first step in a much needed rigorous test of the ‘aluminum hypothesis of Alzheimer's disease’ and a longer term study involving many more individuals is now warranted. Show more

Keywords: Alzheimer's disease, aluminum, body burden, cognitive function, copper, iron, mineral water, silicic acid, silicon, urinary excretion

DOI: 10.3233/JAD-2012-121231

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 423-430, 2013

Authors: Zhang, Yu | Tartaglia, Maria Carmela | Schuff, Norbert | Chiang, Gloria C. | Ching, Christopher | Rosen, Howard J. | Gorno-Tempini, Maria Luisa | Miller, Bruce L. | Weiner, Michael W.

Article Type: Research Article

Abstract: Brain magnetic resonance imaging (MRI) studies have demonstrated regional patterns of brain macrostructural atrophy and white matter microstructural alterations separately in the three major subtypes of frontotemporal lobar degeneration (FTLD), which includes behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). This study was to investigate to what extent the pattern of white matter microstructural alterations in FTLD subtypes mirrors the pattern of brain atrophy, and to compare the ability of various diffusion tensor imaging (DTI) indices in characterizing FTLD patients, as well as to determine whether DTI measures provide greater classification power for FTLD than …measuring brain atrophy. Twenty-five patients with FTLD (13 with bvFTD, 6 with SD, and 6 with PNFA) and 19 healthy age-matched control subjects underwent both structural MRI and DTI scans. Measurements of regional brain atrophy were based on T1-weighted MRI data and voxel-based morphometry. Measurements of regional white matter degradation were based on voxelwise as well as regions-of-interest tests of DTI variations, expressed as fractional anisotropy, axial diffusivity, and radial diffusivity. Compared to controls, bvFTD, SD, and PNFA patients each exhibited characteristic regional patterns of brain atrophy and white matter damage. DTI overall provided significantly greater accuracy for FTLD classification than brain atrophy. Moreover, radial diffusivity was more sensitive in assessing white matter damage in FTLD than other DTI indices. The findings suggest that DTI in general and radial diffusivity in particular are more powerful measures for the classification of FTLD patients from controls than brain atrophy. Show more

Keywords: Behavioral variant frontotemporal dementia, diffusion tensor imaging, frontotemporal lobar degeneration, multimodality MRI, progressive nonfluent aphasia, semantic dementia

DOI: 10.3233/JAD-2012-121156

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 431-444, 2013

Authors: Klein, Eran P. | Kaye, Jeffrey

Article Type: Research Article

Abstract: The goal of this study was to describe the attitudes of U.S. neurologists specializing in dementia toward the use of amyloid imaging in the diagnosis of Alzheimer's disease (AD). A cross-sectional electronic physician survey of dementia specialists at U.S. medical schools was performed. The response rate for the survey was 51.9% (135/260). Greater than 83% of respondents plan to use amyloid imaging to evaluate patients for AD. Most respondents intend to use amyloid imaging as an adjunctive diagnostic modality to confirm (77%) or rule-out (73%) a diagnosis of AD; 24% plan to use amyloid imaging to screen asymptomatic individuals for …evidence of cerebral amyloid. Specialists who do not intend to use amyloid imaging (16%) express concern about the cost (73%), the usefulness (55%), and likelihood of patient (55%) and clinician (59%) misinterpretation of findings. The need for patient pre-test counseling was endorsed by a large percentage (92%) of dementia specialists (higher than for genetic testing (82%)). In conclusion, dementia specialists, particularly young specialists, are likely to be early adopters of amyloid imaging. Assuming ready availability, this new technology would be used as a confirmatory test in the evaluation of AD, as well as a screening tool for asymptomatic pathology. Specialists recognize the complexity of interpreting amyloid imaging findings and the need for patient counseling before undergoing testing. Show more

Keywords: Alzheimer's disease, amyloid, biomarker, dementia, diagnosis, neuroimaging, PET

DOI: 10.3233/JAD-2012-121216

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 445-450, 2013

Authors: Bahar-Fuchs, Alex | Villemagne, Victor | Ong, Kevin | Chetélat, Gaël | Lamb, Fiona | Reininger, Cornelia B. | Woodward, Michael | Rowe, Christopher C.

Article Type: Research Article

Abstract: Assessment of disease biomarkers, particularly the in vivo assessment of amyloid-β (Aβ) burden with positron emission tomography (PET), is gradually becoming central to the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease (AD). However, the incorporation of biomarker evidence to the diagnostic process is currently restricted mainly to research settings. The identification of memory measures that are associated with Aβ is of clinical relevance as this may enhance the confidence in making a diagnosis of MCI due to AD in clinical settings. Forty one persons with amnestic MCI underwent Aβ imaging with 18 F-Florbetaben PET, magnetic resonance imaging, …and a comprehensive neuropsychological assessment. All measures of episodic memory were significantly correlated with Aβ burden, but regression analyses revealed a strong and selective association between story recall and Aβ over and beyond the effects of age, education, global cognition, hippocampal volume, or other memory tests. Analyses of sensitivity and specificity of memory measures to detect high versus low Aβ scans suggested that word-list recall performed better when high sensitivity was preferred, whereas story recall performed better when high specificity was preferred. In conclusion, a measure of story recall may increase the confidence in making a diagnosis of MCI due to AD in clinical settings. Show more

Keywords: Aging, Alzheimer's disease, amyloid imaging, 18F Florbetaben PET, memory, mild cognitive impairment

DOI: 10.3233/JAD-2012-121315

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 451-462, 2013

Authors: Forest, Stefanie K. | Acker, Christopher M. | d'Abramo, Cristina | Davies, Peter

Article Type: Research Article

Abstract: In Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, undergoes a conformational change, and becomes aggregated and insoluble. There are three methods commonly used to study the insoluble tau fraction, two that utilize detergents (Sarkosyl and RIPA) and another that does not (insoluble). However, these methods require large amounts of homogenate for a relatively low yield of the insoluble fraction, which can be problematic when dealing with small tissue samples. Furthermore, the most common way of analyzing this material is through densitometry of immunoblots, offering only semiquantitative measurements. We provide a comparison of the three methods commonly used (Sarksoyl, RIPA, …and insoluble) through immunoblot and ELISA analyses. Finally, we tested a new method to determine aggregated tau levels, utilizing a monoantibody tau ELISA. The insoluble fractions of four different mouse models (P301 L, htau, wild type, and knockout) as well as human AD and control brains were examined. There were significant correlations between the three insoluble methods for both total tau and pS396/404 tau measured by immunoblot or ELISA analyses. Additionally, the results from the ELISA method correlated significantly with those from immunoblot analyses. Finally, the monoantibody assay on the lysate significantly correlated with the total tau ELISAs performed on the three insoluble preparations. Taken together, these results suggest that all three insoluble preparation methods offer similar results for measuring insoluble tau in either mouse or human brains. In addition the new monoantibody ELISA offers a simple quantitative method to measure the amount of aggregated tau in both human and mouse brains. Show more

Keywords: Alzheimer's disease, ELISA, immunoblotting, methodology, tau protein, transgenic mice

DOI: 10.3233/JAD-2012-121354

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 463-471, 2013

Authors: Yew, Belinda | Alladi, Suvarna | Shailaja, Mekala | Hodges, John R. | Hornberger, Michael

Article Type: Research Article

Abstract: Recent studies suggest that significant memory problems are not specific to Alzheimer's disease (AD) but can be also observed in other neurodegenerative conditions, such as behavioral variant frontotemporal dementia (bvFTD). We investigated whether orientation (spatial & temporal) information is a better diagnostic marker for AD compared to memory and whether their atrophy correlates of orientation and memory differ. A large sample (n = 190) of AD patients (n = 73), bvFTD patients (n = 54), and healthy controls (n = 63) underwent testing. A subset of the patients (n = 72) underwent structural imaging using voxel-based morphometry analysis of magnetic …resonance brain imaging. Orientation and memory scores from the Addenbrooke's Cognitive Examination showed that AD patients had impaired orientation and memory, while bvFTD patients performing at control level for orientation but had impaired memory. A logistic regression showed that 78% of patients could be classified on the basis of orientation and memory scores alone at clinic presentation. Voxel-based morphometry analysis was conducted using orientation and memory scores as covariates, which showed that the neural correlates for orientation and memory also dissociated with posterior hippocampus cortex being related to orientation in AD, while the anterior hippocampus was associated with memory performance in the AD and bvFTD patients. Orientation and memory measures discriminate AD and bvFTD to a high degree and tap into different hippocampal regions. Disorientation and posterior hippocampus appears therefore specific to AD and will allow clinicians to discriminate AD patients from other neurodegenerative conditions with similar memory deficits at clinic presentation. Show more

Keywords: Alzheimer's disease, atrophy, frontotemporal dementia, hippocampus, memory, orientation

DOI: 10.3233/JAD-2012-120769

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 473-481, 2013

Authors: Bozzali, Marco | Battistoni, Valentina | Premi, Enrico | Alberici, Antonella | Giulietti, Giovanni | Archetti, Silvana | Turla, Marinella | Gasparotti, Roberto | Cercignani, Mara | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Several causative gene mutations have been identified in frontotemporal lobar degeneration (FTLD), including mutations within Granulin (GRN) genes. It was recently shown that FTLD patients carriers of GRN Thr272fs mutation [FTLD-GRN(m+)] exhibit more severe abnormalities, as assessed by magnetic resonance imaging (MRI), than those with sporadic FTLD [FTLD-GRN(m−)]. The aim of this study was to investigate the relationship between grey (GM) and white matter (WM) microstructural damage in FTLD patients, carriers and non-carriers of the mutation. Twenty-three FTLD patients [6 GRN(m+) and 17 GRN(m−)] and 12 healthy subjects received an MRI scan including volumetric and diffusion imaging. GM was assessed …using voxel-based morphometry, while the corpus callosum was reconstructed using diffusion tractography. Mean diffusivity and fractional anisotropy of the corpus callosum were compared between groups. FTLD patients showed widespread GM atrophy and altered diffusion indices in the corpus callosum when compared to healthy subjects. When contrasting GRN(m+) against GRN(m−) patients, the former group had more atrophy in the left frontal GM, and reduced fractional anisotropy and increased mean diffusivity in the left anterior part of the corpus callosum. Significant correlations between the GM and WM damage were found in GRN(m+) patients. This pattern of damage was able to predict some of the additional neuropsychological deficits observed in GRN(m+) as compared to GRN(m−) patients. A more prominent involvement of WM in GRN(m+) patients is consistent with the knowledge that GRN genes are expressed in the microglia. This involvement might be responsible for the accrual of additional GM atrophy via disconnection mechanisms. Show more

Keywords: Corpus callosum, diffusion tensor magnetic resonance imaging, frontotemporal lobar degeneration, granulin, GRN, tractography, voxel-based morphometry

DOI: 10.3233/JAD-2012-121273

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 483-494, 2013