Journal of Alzheimer's Disease - Volume 39, issue 1

Authors: Timmer, Nienke M. | Metaxas, Athanasios | van der Stelt, Inge | Kluijtmans, Leo A.J. | van Berckel, Bart N. | Verbeek, Marcel M.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) deposition, one of the main hallmarks of Alzheimer's disease (AD), has been linked to glutamatergic dysfunction, i.e., increased stimulation of synaptic glutamate receptors that may ultimately result in neuronal loss. It was our aim to study the effect of Aβ on multiple components of the glutamatergic system, and therefore we assessed the expression of several glutamate-related proteins and amino acids in the TgSwDI mouse model for Aβ pathology. We determined that in TgSwDI mice, levels of several amino acids are altered, in particular that of glycine. Protein changes were only found in 9-month-old TgSwDI mice with extensive Aβ …deposits, with the most prominent change an increased expression of vesicular glutamate transporter 1 (vGlut1). Autoradiography experiments demonstrated that, while the number of activated N-methyl-D-aspartic acid (NMDA) receptors was unchanged in TgSwDI mice, binding of the NMDA receptor radioligand [3 H]MDL-105,519 to the glycine-binding site of these receptors was increased. Although there are some discrepancies between our results and those found in AD patients, our results suggest that several components of the glutamatergic system might serve as meaningful markers to monitor the progression of AD. Show more

Keywords: Alzheimer's disease, amino acid analysis, autoradiography, amyloid-β, glutamate, glycine, TgSwDI mice, vesicular glutamate transporter 1, western blot

DOI: 10.3233/JAD-130437

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 89-101, 2014

Authors: Brugnolo, Andrea | Morbelli, Silvia | Arnaldi, Dario | De Carli, Fabrizio | Accardo, Jennifer | Bossert, Irene | Dessi, Barbara | Famà, Francesco | Ferrara, Michela | Girtler, Nicola | Picco, Agnese | Rodriguez, Guido | Sambuceti, Gianmario | Nobili, Flavio

Article Type: Research Article

Abstract: We evaluated the brain metabolic correlates of main indexes of a widely used word list learning test, the Rey Auditory Verbal Memory Test (RAVLT), in a group of elderly subjects with memory complaints. Fifty-four subjects (age: 72.02 ± 7.45; Mini-Mental State Examination (MMSE) score: 28.9 ± 1.24) presenting at a memory clinic complaining of memory deficit, but not demented, and thirty controls (age: 71.87 ± 7.08; MMSE score: 29.1 ± 1.1) were included. Subjects with memory complaints included both patients with (amnestic mild cognitive impairment, aMCI) and without (subjective memory complaints, SMC) impairment on memory tests. All subjects underwent 18 …F-fluorodeoxyglucose positron emission tomography (FDG-PET), analyzed with statistical parametric. Patients with aMCI but not those with SMC showed the expected posterior cingulate-precuneus and parietal hypometabolism as compared to controls. Correlation was determined for between four indexes of the RAVLT and brain metabolism. The results show a significant correlation between the delayed recall score and metabolism in posterior cingulate gyrus of both hemispheres and in left precuneus, as well as between a score of long-term percent retention and metabolism in left posterior cingulate gyrus, precuneus, and orbitofrontal areas. These correlations survived correction for age, education, and MMSE score. No correlation was found between immediate or total recall scores and glucose metabolism. These data show the relevant role of posterior cingulate-precuneus and orbitofrontal cortices in retention and retrieval of de-contextualized verbal memory material in a group of elderly subjects with memory complaints and shed light on the topography of synaptic dysfunction in these subjects, overlapping that found in the earliest stages of Alzheimer-type neurodegeneration. Show more

Keywords: Brain FDG-PET, memory, mild cognitive impairment, Rey Auditory Verbal Learning Test

DOI: 10.3233/JAD-121684

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 103-113, 2014

Authors: Horvath, Judit | Burkhard, Pierre R. | Herrmann, François R. | Bouras, Constantin | Kövari, Enikö

Article Type: Research Article

Abstract: About one third of Alzheimer's disease (AD) patients develop some parkinsonian features, yet half of them do not have Lewy body pathology at autopsy. The neuropathological substrate of parkinsonism in AD is still unclear. In the present study, we measured neuronal and neurofibrillary tangles (NFTs) densities in the substantia nigra pars compacta (SN) and in the putamen of 22 AD patients, 11 with and 11 without parkinsonism, here defined as the presence of bradykinesia and at least one of resting tremor, rigidity, or gait disorders. Our study showed that parkinsonism associated with AD was related to a significant loss of …neurons both in the SN and in the putamen, suggesting pre-and postsynaptic alterations of the nigrostriatal pathway. Neuronal tau deposition was a less important factor as density of NFTs correlated with parkinsonism only in the SN but not in the putamen. We propose that a subgroup of pure AD patients develop parkinsonian symptoms as a result of neuronal loss in the basal ganglia, indicating a prominent subcortical involvement, which appears unrelated to the Braak stage of AD. Show more

Keywords: Alzheimer's disease, histology, parkinsonism, pathology, putamen, substantia nigra

DOI: 10.3233/JAD-131289

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 115-120, 2014

Authors: Lalande, Julie | Halley, Hélène | Balayssac, Stéphane | Gilard, Véronique | Déjean, Sébastien | Martino, Robert | Francés, Bernard | Lassalle, Jean-Michel | Malet-Martino, Myriam

Article Type: Research Article

Abstract: In the quest for biomarkers of onset and progression of Alzheimer's disease, a 1 H NMR-based metabolomic study was performed on the simple single-transgenic Tg2576 mouse model. These mice develop a slow cognitive decline starting by 6 months and express amyloid plaques from 10 months of age. The metabolic profiles of extracts from five brain regions (frontal cortex, rhinal cortex, hippocampus, midbrain, and cerebellum) of Tg2576 male mice were compared to those of controls, at 1, 3, 6 and 11 months of age. The most obvious differences were due to brain regions. Age was also a discriminating parameter. Metabolic perturbations …were already detected in the hippocampus and the rhinal cortex of transgenic mice as early as 1 month of age with decreased concentrations of glutamate (Glu) and N-acetylaspartate (NAA) compared to those in wild-type animals. Metabolic changes were more numerous in the hippocampus and the rhinal cortex of 3 month-old transgenic mice and involved Glu, NAA, myo-inositol, creatine, phosphocholine, and γ-aminobutyric acid (only in the hippocampus) whose concentrations decreased. A metabolic disruption characterized by an increase in the hippocampal concentrations of Glu, creatine, and taurine was detected in 6 month-old transgenic mice. At this time point, the chemical profile of the cerebellum was slightly affected. At 11 months, all the brain regions analyzed (except the frontal cortex) were metabolically altered, with mainly a marked increase in the formation of the neuroprotective metabolites creatine and taurine. Our findings demonstrate that metabolic modifications occur long before the onset of behavioral impairment. Show more

Keywords: Alzheimer's disease, AβPPswe Tg2576 mouse model, biomarkers, 1H NMR, metabolomics

DOI: 10.3233/JAD-130023

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 121-143, 2014

Authors: Mehla, Jogender | Chauhan, Balwantsinh C. | Chauhan, Neelima B.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type …2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, diabetes, glycogen synthase kinase-3β, learning and memory, pathological aging of the brain, senescence-accelerated mice, synaptophysin, tau

DOI: 10.3233/JAD-131238

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 145-162, 2014

Authors: van Veluw, Susanne J. | Heringa, Sophie M. | Kuijf, Hugo J. | Koek, Huiberdina L. | Luijten, Peter R. | Biessels, Geert Jan | on behalf of the Utrecht Vascular Cognitive Impairment study group

Article Type: Research Article

Abstract: Cerebral microinfarcts (CMIs) are a common finding in neuropathological studies of aging and dementia. Recently, it has become possible to detect CMIs in vivo. We studied CMI occurrence in 29 patients with mild cognitive impairment or early Alzheimer's disease (AD) and 22 non-demented individuals on 7Tesla MRI. CMI occurrence in patients (55%) and controls (45%) was not significantly different. In patients, CMI number tended to be related to microbleed number (p = 0.07). This first in vivo study of CMIs in early AD does not confirm findings from autopsy studies. Further studies are needed to clarify the role of CMIs …in AD. Show more

Keywords: Alzheimer's disease, magnetic resonance imaging, microbleeds, microinfarcts, mild cognitive impairment

DOI: 10.3233/JAD-131040

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 163-167, 2014

Authors: Asti, Annalia | Gioglio, Luciana

Article Type: Research Article

Abstract: Data found in literature have reported that bacterial endotoxins may be involved in the inflammatory and pathological processes associated with amyloidosis and Alzheimer's disease (AD). In fact, it has been observed that the chronic infusion of the bacterial lipopolysaccharide, the outer cell wall component of Gram negative bacteria, into the fourth ventricle of rats reproduces many of the inflammatory and pathological features seen in the brain of AD patients. In this context, a key player in the pathogenesis of AD is the amyloid-β peptide (Aβ) that is capable of aggregating in fibrils that represent the main component of amyloid plaques. …These deposits that accumulate among brain cells are indeed one of the hallmarks of AD. This aggregation in fibrils seems to correlate with Aβ toxic effects. However, recent data have shown that amyloid fibril formation not only results in toxic aggregates but also provides biologically functional molecules; such amyloids have been identified on the surface of fungi and bacteria. The aim of this work was to gain insight into the influence of bacterial endotoxins on Aβ fibrillogenesis; factors that influence fibril formation may be important for Aβ toxic potential. Following three days of incubation at 37°C, Aβ was organized in compact fibrils and the in vitro Aβ fibrillogenesis was potentiated by the Escherichia coli endotoxin. This suggests the importance of infectious events in the pathogenesis of AD and proposes a new aspect related to the putative pathological factors that can be implicated in the mechanisms involved in Aβ25-35 fibrillogenesis. Show more

Keywords: Alzheimer's disease, amyloid-β, lipopolysaccharide, Escherichia coli, transmission electron microscopy

DOI: 10.3233/JAD-131394

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 169-179, 2014

Authors: Boucart, Muriel | Bubbico, Giovanna | Szaffarczyk, Sébastien | Pasquier, Florence

Article Type: Research Article

Abstract: We investigated rapid object categorization and, more specifically, the ability to detect a target object within a natural scene in people with mild Alzheimer's disease (AD) using a saccadic choice task. It has been suggested that the anatomical pathway likely used to initiate rapid oculomotor responses in the saccadic choice task could involve the Frontal Eye Field, a structure that is part of the dorsal attentional network, in which connectivity is disrupted in AD. Seventeen patients with mild AD and 23 healthy age-matched controls took part in the study. A group of 24 young healthy observers was included as it …has been reported that normal aging affects eye movements. Participants were presented with pairs of colored photographs of natural scenes, one containing an animal (the target) and one containing various objects (distracter), displayed for 1 s left and right of fixation. They were asked to saccade to the scene containing an animal. Neither pathology nor age affected temporal (saccade latencies and durations) and spatial (saccade amplitude) parameters of eye movements. Patients with AD were significantly less accurate than age-matched controls, and older participants were less accurate than young observers. The results are interpreted in terms of noisier sensory information and increased uncertainty in relation to deficits in the magnocellular pathway. The results suggest that, even at a mild stage of the pathology, people exhibit difficulties in selecting relevant objects. Show more

Keywords: Alzheimer's disease, eye movements, saccade, scene perception

DOI: 10.3233/JAD-131331

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 181-189, 2014

Authors: Marchese, Monica | Cowan, David | Head, Elizabeth | Ma, Donglai | Karimi, Khalil | Ashthorpe, Vanessa | Kapadia, Minesh | Zhao, Hui | Davis, Paulina | Sakic, Boris

Article Type: Research Article

Abstract: Background: Immune system activation is frequently reported in patients with Alzheimer’s disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. Objective: The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. Methods: A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. Results: Aged AD mice displayed severe manifestations …of systemic autoimmune/inflammatory dise6ase, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology. Conclusion: The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD. Show more

Keywords: Alzheimer's disease, amyloidosis, anxiety, autoimmunity, hepatomegaly, inflammation, mild cognitive impairment, olfaction, splenomegaly, 3xTg-AD model

DOI: 10.3233/JAD-131490

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 191-210, 2014

Authors: Milward, Elizabeth A. | Moscato, Pablo | Riveros, Carlos | Johnstone, Daniel M.

Article Type: Research Article

Abstract: Interventions to delay or slow Alzheimer's disease (AD) progression are most effective when implemented at pre-clinical disease stages, making early diagnosis essential. For this reason, there is an increasing focus on discovery of predictive biomarkers for AD. Currently, the most reliable predictive biomarkers require either expensive (brain imaging) or invasive (cerebrospinal fluid collection) procedures, leading researchers to strive toward identifying robust biomarkers in blood. Yet promising early results from candidate blood biomarker studies are being refuted by subsequent findings in other cohorts or using different assay technologies. Recent evidence suggests that univariate blood biomarkers are not sufficiently sensitive or specific …for the diagnosis of disorders as complex, multifactorial, and heterogeneous as AD. To overcome these present limitations, more consideration must be given to the development of ‘biomarker panels’ assessing multiple molecular entities. The selection of such panels should draw not only on traditional statistical approaches, whether parametric or non-parametric, but also on newer non-statistical approaches that have the capacity to retain and utilize information about all individual study participants rather than collapsing individual data into group summary values (e.g., mean, variance). These new approaches, facilitated by advances in computing, have the potential to preserve the context of interrelationships between different molecular entities, making them amenable to the development of panels that, as a multivariate collective, can overcome the challenge of individual variability and disease heterogeneity to accurately predict and classify AD. We argue that the AD research community should take fuller advantage of these approaches to accelerate discovery. Show more

Keywords: Biomarker, blood, combinatorial optimization, multivariate, non-statistical

DOI: 10.3233/JAD-131424

Citation: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 211-217, 2014