Journal of Alzheimer's Disease - Volume 31, issue 1

Authors: Capsoni, Simona | Carucci, Nicola Maria | Cattaneo, Antonino

Article Type: Short Communication

Abstract: Several studies suggest that systemic infection occurring during aging and chronic neurodegenerative diseases can evoke an exaggerated immune response that contributes to the progression of neurodegeneration and cognitive decline. However, studies directly addressing the relationship between microbial environment and the onset of neurodegeneration in Alzheimer's disease animal models are lacking. Here we show that the onset of neurodegeneration that transgenic mice develop when raised in conventional husbandry slows down when raising anti-nerve growth factor transgenic mice in a murine pathogen free condition.

Keywords: Amyloid-β, deprivation, interleukin-6, microglia, murine pathogen free, nerve growth factor, phosphorylated tau, systemic inflammation

DOI: 10.3233/JAD-2012-120427

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 1-6, 2012

Authors: Testi, Silvia | Fabrizi, Gian Maria | Pompanin, Sara | Cagnin, Annachiara

Article Type: Short Communication

Abstract: Mutations in the Presenilin 2 gene (PSEN2) represent the less frequent genetic cause of familial Alzheimer's disease (FAD). Only eight PSEN2 mutations, reported in approximately 27 families, satisfied strict criteria of pathogenicity. We reported a patient with early-onset FAD and the PSEN2 p.Met239Ile mutation, presenting with severe executive dysfunction and myoclonic tremor, associated with memory loss. Brain SPECT study showed an early hypoperfusion of the frontal cortex. We confirmed the pathogenicity of PSEN2 p.Met239Ile mutation and its heterogeneous phenotypic expression. The modulating effect of the Apolipoprotein E and Prion Protein gene polymorphisms on the phenotypic variability was not confirmed.

Keywords: Alzheimer's disease, familial, frontal lobe, mutation, Presenilin 2

DOI: 10.3233/JAD-2012-120280

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 7-11, 2012

Authors: Perret-Liaudet, Armand | Pelpel, Mathieu | Tholance, Yannick | Dumont, Benoit | Vanderstichele, Hugo | Zorzi, Willy | ElMoualij, Benaissa | Schraen, Susanna | Moreaud, Olivier | Gabelle, Audrey | Thouvenot, Eric | Thomas-Anterion, Catherine | Touchon, Jacques | Krolak-Salmon, Pierre | Kovacs, Gabor G. | Coudreuse, Arnaud | Quadrio, Isabelle | Lehmann, Sylvain

Article Type: Research Article

Abstract: Tau proteins and amyloid-β (Aβ) peptides are the current recognized cerebrospinal fluid (CSF) biomarkers used as an aid in the diagnosis of Alzheimer's disease (AD). However, there is no consensus on their clinical use due to non-qualified cut-off values, probably related to the observed high pre-analytical and analytical variability. Standardized pre-analytical protocols have therefore been proposed. Importantly, these recommend the use of polypropylene collection/sampling tubes while, to date, no broad comparison of these types of tubes has been conducted. In this study, we first compared, as part of a real clinical workflow, the impact of four different collection tubes on …the CSF concentration of Aβ peptides (Aβ42 , Aβ40 ) and total (hTau) and phosphorylated (P-Tau181P) tau proteins measured using routine ELISA kits. We then extended this study to 11 polypropylene tubes used by different clinical laboratories, and investigated their plastic polymer composition using differential scanning calorimetry and Fourier Transformed Infrared spectroscopy. Significant concentration variations linked solely to the use of different types of tubes were observed. This was particularly marked for Aβ peptides, with >50% disparity occurring in less than five minutes. Polymer composition analysis revealed that most polypropylene tubes were in fact copolymers with at least polyethylene. There was no clear correlation between tube composition and pre-analytical behavior. Our results show that the use of polypropylene tubes does not guarantee satisfactory pre-analytical behavior. They also point to collection/sampling tubes being a major pre-analytical source of variability that could impact the significance of AD biological diagnosis. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, collection tubes, standardization

DOI: 10.3233/JAD-2012-120361

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 13-20, 2012

Authors: Eckert, Schamim H. | Eckmann, Janett | Renner, Kathrin | Eckert, Gunter P. | Leuner, Kristina | Muller, Walter E.

Article Type: Research Article

Abstract: Due to their role in producing energy, as major sources of free radicals, and as critical regulators of apoptosis, mitochondria play a dominant role in the central nervous system (CNS). Mitochondrial dysfunction represents one major pathomechanism of Alzheimer's disease (AD), including impaired function of mitochondrial respiratory chain complexes and deficits of mitochondrial dynamics, such as impaired balance between fission and fusion mechanisms and reduced mitochondrial trafficking. Major consequences are enhanced depletion of mitochondria in axons and dendrites, synaptic dysfunction, and finally neuronal loss. Interfering with impaired mitochondrial dynamics has been proposed as novel strategy for antidementia drugs. Dimebon has been …shown to improve cognition in animal models and seems to be beneficial in AD patients. Regardless of the final proof of Dimebon's clinical efficacy, it might specifically interfere with mechanisms relevant for the cognitive decline, especially by improving impaired mitochondrial function and/or dynamics in AD. Herein, we tested the effects of Dimebon on mitochondrial function and dynamics in a cellular model, overexpressing neurotoxic Aβ peptides, one of the hallmarks of AD. Dimebon exerted pronounced effects on mitochondrial morphology, respiratory chain complex activities, and enlarged mitochondrial mass. In summary, form and function of mitochondria are altered in the Aβ overexpressing cell model and precisely those changes are restored by nanomolar Dimebon treatment. Our findings support the idea that Dimebon improves mitochondrial function and that these “disease specific” effects might be relevant for interpretation and planning of future clinical trials. Show more

Keywords: Alzheimer's disease, amyloid-β, AβPP mutation, Dimebon, latrepirdine, mitochondrial dynamics, mitochondrial dysfunction, mitochondrial mass, mitochondrial morphology, mitochondrial respiratory complexes, OXPHOS

DOI: 10.3233/JAD-2012-120310

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 21-32, 2012

Authors: Mak, Henry K.F. | Chan, Queenie | Zhang, Zhipeng | Petersen, Esben T. | Qiu, Deqiang | Zhang, Linda | Yau, Kelvin K.W. | Chu, Leung-Wing | Golay, Xavier

Article Type: Research Article

Abstract: QUASAR arterial spin labeling (ASL) was used to investigate the role of vascular impairment in Alzheimer's disease (AD). We hypothesized that the hemodynamic parameters monitoring cerebrovascular integrity, i.e., cerebral blood flow (CBF), arterial blood volume (aBV), and arterial transit time (aTT), would be affected. 13 AD patients and 15 healthy control (HC) subjects underwent 3T MRI scanning. Two separate blood flow acquisitions were obtained with 1 slice overlap for whole brain coverage. CBF, aBV, and aTT maps were calculated using in-house software. Preprocessing and statistical analyses were performed on SPM5. Region-of-interest (ROI) studies of ten selected cerebral regions were also …conducted. There were significant differences in Mini Mental Status Exam (MMSE) (AD: 16.3 ± 4.55, HC: 28.5 ± 2.00) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores (AD: 25.25 ± 9.64, HC: 5.51 ± 2.62) between the 2 groups (p < 0.001) but none in age (p = 0.068). CBF decreased significantly (p < 0.01) in AD compared to controls in the right middle cingulate, left cuneus, left inferior and middle frontal, right superior frontal, left inferior parietal, and right supramarginal gyri. ROI studies confirmed significant hemodynamic impairments in AD compared to HC (p < 0.05): CBF in middle and posterior cingulate, aBV in left superior temporal, right inferior parietal, and posterior cingulate, and aTT in left inferior frontal and middle cingulate gyri. CBF correlated positively while aTT correlated negatively to MMSE, and vice versa for ADAS-cog. Using QUASAR ASL, we found patterns of regional hemodynamic impairment typical of moderate AD, suggesting underlying vascular abnormality. As potential biomarkers, these hemodynamic parameters could differentiate patients from volunteers, and possibly indicate the conversion from healthy aging to mild cognitive impairment to AD. Show more

Keywords: Alzheimer's disease, arterial blood volume, arterial spin labeling, arterial transit time, cerebral blood flow, magnetic resonance imaging, mild cognitive impairment, QUASAR

DOI: 10.3233/JAD-2012-111877

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 33-44, 2012

Authors: Squarzoni, Paula | Tamashiro-Duran, Jaqueline | Souza Duran, Fabio Luiz | Santos, Luciana Cristina | Vallada, Homero Pinto | Menezes, Paulo Rossi | Scazufca, Marcia | Filho, Geraldo Busatto | Alves, Tania Correa Toledo de Ferraz

Article Type: Research Article

Abstract: The presence of cognitive impairment is a frequent complaint among elderly individuals in the general population. This study aimed to investigate the relationship between aging-related regional gray matter (rGM) volume changes and cognitive performance in healthy elderly adults. Morphometric magnetic resonance imaging (MRI) measures were acquired in a community-based sample of 170 cognitively-preserved subjects (66 to 75 years). This sample was drawn from the “São Paulo Ageing and Health” study, an epidemiological study aimed at investigating the prevalence and risk factors for Alzheimer's disease in a low income region of the city of São Paulo. All subjects underwent cognitive testing …using a cross-culturally battery validated by the Research Group on Dementia 10/66 as well as the SKT (applied on the day of MRI scanning). Blood genotyping was performed to determine the frequency of the three apolipoprotein E allele variants (APOE ε2/ε3/ε4) in the sample. Voxelwise linear correlation analyses between rGM volumes and cognitive test scores were performed using voxel-based morphometry, including chronological age as covariate. There were significant direct correlations between worse overall cognitive performance and rGM reductions in the right orbitofrontal cortex and parahippocampal gyrus, and also between verbal fluency scores and bilateral parahippocampal gyral volume (p < 0.05, familywise-error corrected for multiple comparisons using small volume correction). When analyses were repeated adding the presence of the APOE ε4 allele as confounding covariate or excluding a minority of APOE ε2 carriers, all findings retained significance. These results indicate that rGM volumes are relevant biomarkers of cognitive deficits in healthy aging individuals, most notably involving temporolimbic regions and the orbitofrontal cortex. Show more

Keywords: Cognitive decline, healthy aging, structural MRI, voxel-based morphometry

DOI: 10.3233/JAD-2012-111124

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 45-58, 2012

Authors: Hasegawa, Tohru | Ichiba, Masayoshi | Matsumoto, Shin-ei | Kasanuki, Koji | Hatano, Taku | Fujishiro, Hiroshige | Iseki, Eizo | Hattori, Nobutaka | Yamada, Tatsuo | Tabira, Takeshi

Article Type: Research Article

Abstract: Homocysteic acid (HA) has been suggested as a pathogen in a mouse model of Alzheimer's disease (AD), 3xTg-AD. However, it is not established whether HA is involved in humans. We investigated the relationship between urinary HA levels and Mini-Mental State Examination (MMSE) scores in AD patients (n = 70) and non-AD controls (n = 34). We found a positive, statistically significant relationship between the two variables (the urinary HA level and MMSE score) (r = 0.31, p = 0.0008, n = 70). This relationship was stronger in females than males (r = 0.43, p = 0.005, n = 44 in …females; r = 0.48, p = 0.02, n = 22 in males). The urinary HA levels were significantly different in AD patients than controls (AD: 8.7 ± 7.5, n = 70; non-dementia control: 13.3 ± 9.4, n = 34, p < 0.01). In addition, aging and smoking were found as lowering factors for urinary HA levels. Our preliminary study showed a negative, statistically significant relationship between blood HA (micromole) and urine HA levels (r = −0.6, p = 0.007, n = 19), and between blood HA levels and MMSE scores (r = −0.79, p = 0.0000518, n = 19). On the basis of these results, we speculate that reduced urinary excretion induces elevated HA levels in blood, resulting in cognitive dysfunctions. This study also suggests that HA may be a candidate of neurotoxins for uremic encephalopathy. Since amyloid-β increases HA toxicity and HA is an agonist of N-methyl-D-aspartic acid (NMDA) receptor, we speculate that elevated blood HA affects the brain cognitive function through NMDA receptor-mediated toxicity in AD. Show more

Keywords: Aging, Alzheimer disease, homocysteic acid, MMSE, smoking, uremia

DOI: 10.3233/JAD-2012-120022

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 59-64, 2012

Authors: Farías, Gonzalo | Pérez, Patricio | Slachevsky, Andrea | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Platelets are major reservoirs of circulating amyloid-β and amyloid-β protein precursor (AβPP) and have been postulated as a reliable source for biological markers of Alzheimer's disease (AD). We have recently demonstrated that tau is also present in platelets, and that there are differences in the electrophoretic patterns of platelet tau forms in AD subjects with respect to controls. Here, we demonstrate that modifications in platelet tau forms occur independently of age in a broad population of 104 neurologically healthy individuals. More interesting, a strong correlation of platelet markers with the degree of cognitive impairment was evidenced in a group of …47 AD patients in comparison with 19 cognitive healthy subjects. In our series, platelet tau forms ratio had a sensitivity of 75.7% and specificity of 73.7%, respectively. We also found that platelet tau displays a significantly higher correlation with the presence of AD than the analyses of platelet AβPP. Show more

Keywords: Alzheimer's disease, cognitive impairment, human platelets, tau biomarker

DOI: 10.3233/JAD-2012-120304

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 65-69, 2012

Authors: Bengtsson, Sara K. | Johansson, Maja | Bäckström, Torbjörn | Wang, Mingde

Article Type: Research Article

Abstract: The endogenous neurosteroid allopregnanolone alters neuronal excitability via modulation of the GABAA receptor and causes decreased neurotransmission. In Alzheimer's disease (AD), neurotransmission seems to alter the levels of toxic intracellular amyloid-β (Aβ) oligomers, which are implicated in AD pathogenesis and cause cognitive decline. Inhibition of synaptic activity has been shown to increase levels of intracellular Aβ. Allopregnanolone at endogenous stress levels inhibits synaptic activity and could have similar effects. By using a transgenic AβPPSwe PSEN1ΔE9 mouse model for AD, we observed that chronic allopregnanolone treatment for three months with stress levels of allopregnanolone impaired learning in the Morris …water maze. The learning impairment was seen one month after the end of treatment. Chronic allopregnanolone treatment also led to increased levels of soluble Aβ in the brain, which could be a sign of advanced pathogenesis. Since the learning and memory of wild-type mice was not affected by the treatment, we propose that chronic allopregnanolone treatment accelerates the pathogenesis of AD. However, further studies are required in order to determine the underlying mechanism. Show more

Keywords: Allopregnanolone, Alzheimer's disease, amyloid-β, amyloid-β1-40, amyloid-β1-42, cognition, physiological stress

DOI: 10.3233/JAD-2012-120268

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 71-84, 2012

Authors: Pluta, John | Yushkevich, Paul | Das, Sandhitsu | Wolk, David

Article Type: Research Article

Abstract: The measurement of hippocampal volumes using MRI is a useful in-vivo biomarker for detection and monitoring of early Alzheimer's disease (AD), including during the amnestic mild cognitive impairment (a-MCI) stage. The pathology underlying AD has regionally selective effects within the hippocampus. As such, we predict that hippocampal subfields are more sensitive in discriminating prodromal AD (i.e., a-MCI) from cognitively normal controls than whole hippocampal volumes, and attempt to demonstrate this using a semi-automatic method that can accurately segment hippocampal subfields. High-resolution coronal-oblique T2-weighted images of the hippocampal formation were acquired in 45 subjects (28 controls and 17 a-MCI (mean age: …69.5 ± 9.2; 70.2 ± 7.6)). CA1, CA2, CA3, and CA4/DG subfields, along with head and tail regions, were segmented using an automatic algorithm. CA1 and CA4/DG segmentations were manually edited. Whole hippocampal volumes were obtained from the subjects' T1-weighted anatomical images. Automatic segmentation produced significant group differences in the following subfields: CA1 (left: p = 0.001, right: p = 0.038), CA4/DG (left: p = 0.002, right: p = 0.043), head (left: p = 0.018, right: p = 0.002), and tail (left: p = 0.019). After manual correction, differences were increased in CA1 (left: p < 0.001, right: p = 0.002), and reduced in CA4/DG (left: p = 0.029, right: p = 0.221). Whole hippocampal volumes significantly differed bilaterally (left: p = 0.028, right: p = 0.009). This pattern of atrophy in a-MCI is consistent with the topography of AD pathology observed in postmortem studies, and corrected left CA1 provided stronger discrimination than whole hippocampal volume (p = 0.03). These results suggest that semi-automatic segmentation of hippocampal subfields is efficient and may provide additional sensitivity beyond whole hippocampal volumes. Show more

Keywords: Automatic segmentation, CA1, hippocampal subfields, mild cognitive impairment, magnetic resonance imaging

DOI: 10.3233/JAD-2012-111931

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 85-99, 2012