Journal of Alzheimer's Disease - Volume 34, issue 4

Authors: Wierenga, Christina E. | Clark, Lindsay R. | Dev, Sheena I. | Shin, David D. | Jurick, Sarah M. | Rissman, Robert A. | Liu, Thomas T. | Bondi, Mark W.

Article Type: Research Article

Abstract: We investigated the impact of APOE genotype on cerebral blood flow (CBF) in older and younger adults. Forty cognitively normal older adults (16 ε4 carriers, 24 non-ε4 carriers) and 30 younger adults (15 ε4 carriers, 15 non-ε4 carriers) completed a resting-state whole-brain pulsed arterial spin labeling magnetic resonance scan. Main effects of aging were demonstrated wherein older adults had decreased gray matter CBF corrected for partial volume effects compared to younger adults in widespread brain regions. Main effects of APOE genotype were also observed wherein ε4 carriers displayed greater CBF in the left lingual gyrus and precuneus than non-carriers. An …interaction between age and APOE genotype in the left anterior cingulate cortex (ACC) was characterized by reduced CBF in older ε4 carriers and increased CBF in young ε4 carriers. Increased CBF in the left ACC resulting from the interaction of age group and APOE genotype was positively correlated with executive functioning in young ε4 adults (r = 0.61, p = 0.04). Results demonstrate APOE genotype differentially impacts cerebrovascular function across the lifespan and may modify the relationship between CBF and cognition. Findings may partially support suggestions that the gene exerts antagonistic pleiotropic effects. Show more

Keywords: Aging, antagonistic pleiotropy, apolipoprotein E, cerebral blood flow, cerebrovascular function

DOI: 10.3233/JAD-121897

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 921-935, 2013

Authors: Zhou, Yanping | Luo, Yi | Dai, Jiapei

Article Type: Research Article

Abstract: Axonopathy is closely linked to and promotes diabetic peripheral neuropathy and a subset of neurological diseases including Alzheimer's disease (AD), but its involvement in the development of diabetic encephalopathy remains unknown. In the present study, we aimed to ascertain the role of axonopathy in the development of diabetic encephalopathy and the possible relationship between diabetic encephalopathy and AD. The streptozotocin (STZ)-induced diabetic rat model was used. A Y-maze task, in vivo neuronal tracing, immunohistochemistry, and western blot analysis were performed to evaluate the cognitive functions, axonal and dendritic changes, and the expressions of amyloid-β (Aβ) and hyperphosphorylated tau in relation …to the development of diabetic encephalopathy in this diabetic model. Coincident with significant memory impairment, the diabetic rats showed obvious axonal and dendritic changes, termed axonopathy and dendropathy, respectively, which mainly manifested as the swelling of axons, varicosities, and dendrites in the cognitive-associated brain regions compared to the non-diabetic animals. The site-specific hyperphosphorylated tau, but not deposits of Aβ, was detected in the diabetic rat brains. These data reveal a key role of axonopathy and dendropathy accompanied with the site-specific hyperphosphorylated tau in the course of diabetic encephalopathy, which may be the early link to the neuropathological processes of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, axonopathy, cognitive impairment, diabetes complications, diabetes mellitus, tau protein

DOI: 10.3233/JAD-121762

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 937-947, 2013

Authors: Rolstad, Sindre | Berg, Anne Ingeborg | Bjerke, Maria | Johansson, Boo | Zetterberg, Henrik | Wallin, Anders

Article Type: Research Article

Abstract: The ability to predict future decline in cognitive systems using the cerebrospinal fluid (CSF) biomarkers 42 amino acid form of amyloid-β (Aβ42 ) and total tau (T-tau) is not fully understood. In a clinical sample ranging from cognitively healthy to dementia (n = 326), linear regression models were performed in order to investigate the ability of CSF biomarkers to predict cognitive decline in all cognitive domains from baseline to 2-year follow-up. Gender, age, and years of education were included as covariates. In patients with subjective cognitive impairment, T-tau had a small impact on executive functions (r2 = 0.07). T-tau …had a small to moderate influence (r2 = 0.06–0.11) on all cognitive functions with the exception of visuospatial functions in patients with mild cognitive impairment (MCI). In patients with dementia, the impact of T-tau was large (r2 = 0.29) on semantic memory. Aβ42 had a small effect (r2 = 0.07) on speed and executive functions in MCI. In patients with dementia, Aβ42 had a moderate influence (r2 = 0.13–0.24) on semantic and verbal working memory/fluency. Our results speak in favor of the notion that CSF biomarkers reflect the rate of cognitive decline across the continuum of cognitive impairment from healthy to dementia. CSF predicted subsequent decline in more cognitive domains among MCI cases, but the impact was most pronounced in patients with dementia. Show more

Keywords: Aging, Alzheimer's disease, cerebrospinal fluid, cognition, cognitive decline, dementia, mild cognitive impairment

DOI: 10.3233/JAD-121960

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 949-956, 2013

Authors: Nyborg, Andrew C. | Moll, Jonathan R. | Wegrzyn, Renee D. | Havas, Daniel | Hutter-Paier, Birgit | Feuerstein, Giora G.Z. | Rudolph, Alan S.

Article Type: Research Article

Abstract: Accumulation of amyloid-β (Aβ) cascade aggregates is considered a hallmark of Alzheimer's disease (AD). Current dogma holds that the appearance of Aβ oligomers and larger aggregates occur many years prior to plaque formation associated with the advanced and irreparable neurocognitive decline characteristic of AD. This premise is the impetus to identify these Aβ precursor structures prior to advanced plaque development. The Pronucleon™ technology platform is comprised of a novel series of engineered peptides that provide a unique readout when associated with beta-rich fiber and oligomeric Aβ. This technology has been applied to Ex Vivo tissue sections and In Vivo mouse …models of AD to determine the potential utility of these synthetic peptides as potential imaging agents. In Ex Vivo studies, the Pronucleon™ peptide binds plaque like structures in brain sections obtained from transgenic mice overexpressing hAPP with both the human Swedish and London Aβ mutations. In Vivo, Pronucleon™ peptide administered peripherally can localize to the brain and label plaques throughout the brain in transgenic mice. Taken together, the data suggest that Pronucleon™ could provide a new imaging tool for Aβ cascade elements that precede advanced plaque and fibril formation, thereby advancing early diagnosis and treatment opportunities. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, amyloid-β protein, imaging, oligomer, plaques, senile plaques

DOI: 10.3233/JAD-122107

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 957-967, 2013

Authors: Zhu, David C. | Majumdar, Shantanu | Korolev, Igor O. | Berger, Kevin L. | Bozoki, Andrea C.

Article Type: Research Article

Abstract: We applied a multi-modal imaging approach to examine structural and functional alterations in the default-mode network (DMN) that are associated with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a transitional phase between healthy cognitive aging and dementia. Subjects included 10 patients with probable AD, 11 patients with aMCI, and 12 age- and education-matched normal controls (NC). Whole-brain resting-state functional, diffusion-weighted, and volumetric magnetic resonance imaging (MRI) data as well as 18 F-fluorodeoxyglucose-based positron emission tomography (FDG-PET) data were acquired. We carried out resting-state functional MRI-based functional connectivity and diffusion MRI-based structural connectivity analyses using isthmus of the cingulate …cortex (ICC) and the subjacent white matter as the seeds. Whole-brain group and region of interest-based analyses demonstrated that AD weakens the structural and functional connections between ICC and other regions within the DMN, consistent with regional reduction of metabolic activity and atrophy within the DMN. A progressive weakening trend of these connections was also observed from NC to aMCI and then AD, although significant differences between aMCI and the other two groups were not found. Overall, based on both FDG-PET and MRI results, the DMN appears to serve as a window to understanding structural and functional brain changes associated with AD and aMCI. Show more

Keywords: Alzheimer's disease, default-mode network, diffusion MRI, FDG-PET, mild cognitive impairment, multi-modal imaging, resting-state fMRI

DOI: 10.3233/JAD-121879

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 969-984, 2013

Authors: Wang-Dietrich, Lei | Funke, Susanne Aileen | Kühbach, Katja | Wang, Kun | Besmehn, Astrid | Willbold, Sabine | Cinar, Yeliz | Bannach, Oliver | Birkmann, Eva | Willbold, Dieter

Article Type: Research Article

Abstract: Recent studies indicate that small amyloid-β peptide (Aβ) oligomers are the major toxic species responsible for development and progression of Alzheimer's disease (AD). Therefore, we suggest that the number of Aβ oligomers in body fluids is the most direct and relevant biomarker for AD. Determination of the Aβ oligomer content of cerebrospinal fluid (CSF) samples from 14 AD patients and 12 age-matched controls revealed a clear distinction between both groups. All samples of the control group showed homogenously low numbers of Aβ oligomers, while the samples of the AD group exhibited significantly higher levels of Aβ oligomers. The Aβ oligomer …numbers correlated with the patients' Mini-Mental State Examination scores. This indicates that the quantity of Aβ oligomers in CSF reflects the severity of the disease and that Aβ oligomers play a crucial role in AD pathology and in turn can be used as a diagnostic biomarker. Show more

Keywords: Alzheimer disease, amyloid-β peptide, early diagnosis, sFIDA, surface based fluorescence intensity distribution analysis

DOI: 10.3233/JAD-122047

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 985-994, 2013

Authors: Blazquez-Llorca, Lidia | Merchán-Pérez, Ángel | Rodríguez, José-Rodrigo | Gascón, Jorge | DeFelipe, Javier

Article Type: Research Article

Abstract: The quantification and measurement of synapses is a major goal in the study of brain organization in both health and disease. Serial section electron microscopy (EM) is the ideal method since it permits the direct quantification of crucial features such as the number of synapses per unit volume or the distribution and size of synapses. However, a major limitation is that obtaining long series of ultrathin sections is extremely time-consuming and difficult. Consequently, quantitative EM studies are scarce and the most common method employed to estimate synaptic density in the human brain is indirect, by counting at the light microscopic …level immunoreactive puncta using synaptic markers. The recent development of automatic EM methods in experimental animals, such as the combination of focused ion beam milling and scanning electron microscopy (FIB/SEM), are opening new avenues. Here we explored the utility of FIB/SEM to examine the cerebral cortex of Alzheimer's disease patients. We found that FIB/SEM is an excellent tool to study in detail the ultrastructure and alterations of the synaptic organization of the human brain. Using this technology, it is possible to reconstruct different types of plaques and the surrounding neuropil to find new aspects of the pathological process associated with the disease, namely; to count the exact number and types of synapses in different regions of the plaques, to study the spatial distribution of synapses, and to analyze the morphology and nature of the various types of dystrophic neurites and amyloid deposits. Show more

Keywords: Amyloid-β plaques, asymmetric synapses, autopsy material, automatic electron microscopy, cerebral cortex, dystrophic neurites, symmetric synapses, ultrastructure

DOI: 10.3233/JAD-122038

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 995-1013, 2013

Authors: Babiloni, Claudio | Lizio, Roberta | Del Percio, Claudio | Marzano, Nicola | Soricelli, Andrea | Salvatore, Elena | Ferri, Raffaele | Cosentino, Filomena I.I. | Tedeschi, Gioacchino | Montella, Patrizia | Marino, Silvia | De Salvo, Simona | Rodriguez, Guido | Nobili, Flavio | Vernieri, Fabrizio | Ursini, Francesca | Mundi, Ciro | Richardson, Jill C. | Frisoni, Giovanni B | Rossini, Paolo M.

Article Type: Research Article

Abstract: Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with Alzheimer's disease (AD). Here we tested the hypothesis that these sources are also sensitive to the progression of early stage AD over the course of one year. The resting state eyes-closed EEG data were recorded in 88 mild AD patients at baseline (Mini Mental State Evaluation, MMSE I = 21.7 ± 0.2 standard error, SE) and at approximately one-year follow up (13.3 months ± 0.5 SE; MMSE II = 20 ± 0.4 SE). All patients received standard therapy with acetylcholinesterase inhibitors. EEG recordings were also performed in …35 normal elderly (Nold) subjects as controls. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), beta 2 (20–30 Hz), and gamma (30–40 Hz). Cortical EEG sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Compared to the Nold subjects, the mild AD patients were characterized by a power increase of widespread delta sources and by a power decrease of posterior alpha sources. In the mild AD patients, the follow-up EEG recordings showed increased power of widespread delta sources as well as decreased power of widespread alpha and posterior beta 1 sources. These results suggest that the resting state EEG sources were sensitive, at least at group level, to the cognitive decline occurring in the mild AD group over a one-year period, and might represent cost-effective and non-invasive markers with which to enrich cohorts of AD patients that decline faster for clinical studies. Show more

Keywords: Alzheimer's disease, disease progression, electroencephalography, low resolution brain electromagnetic tomography (LORETA)

DOI: 10.3233/JAD-121750

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 1015-1035, 2013

Authors: Nabuurs, Rob J.A. | Natté, Remco | de Ronde, Fenna M. | Hegeman-Kleinn, Ingrid | Dijkstra, Jouke | van Duinen, Sjoerd G. | Webb, Andrew G. | Rozemuller, Annemieke J. | van Buchem, Mark A. | van der Weerd, Louise

Article Type: Research Article

Abstract: Cerebral deposits of amyloid-β peptides (Aβ) form the neuropathological hallmarks of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In the brain, Aβ can aggregate as insoluble fibrils present in amyloid plaques and vascular amyloid, or as diffuse plaques consisting of mainly non-fibrillar Aβ. Previously, magnetic resonance imaging (MRI) has been shown to be capable of detecting individual amyloid plaques, not only via the associated iron, but also Aβ itself has been suggested to be responsible for a decrease in the image intensity. In this current study we aim to investigate the MRI properties of the different cerebral Aβ deposits …including diffuse plaques and vascular amyloid. Postmortem 60-μm-thick brain sections of AD, CAA, and Down's syndrome patients, known to contain Aβ, were studied. High resolution T2 *- and T2 -weighted MRI scans and quantitative relaxation maps were acquired using a microcoil on a Bruker 9.4T MRI system. Specific MRI characteristics of each type of Aβ deposit were examined by co-registration of the MRI with Congo Red and Aβ-immunostainings of the same sections. Our results show that only fibrillar Aβ, present in both vascular and parenchymal amyloid, induced a significant change in T2 * and T2 values. However, signal changes were not as consistent for all of the vessels affected by CAA, irrespective of possible dyshoric changes. In contrast, the non-fibrillar diffuse plaques did not create any detectable MRI signal changes. These findings are relevant for the interpretation and further development of (quantitative) MRI methods for the detection and follow-up of AD and CAA. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid plaque, cerebral amyloid angiopathy, magnetic resonance imaging

DOI: 10.3233/JAD-122215

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 1037-1049, 2013

Authors: van Duijn, Sara | Nabuurs, Rob J.A. | van Duinen, Sjoerd G. | Natté, Remco | van Buchem, Mark A. | Alia, A.

Article Type: Research Article

Abstract: Epidemiological studies indicate that the incidence of Alzheimer's disease (AD) is higher in women than in men. There is evidence that changes in metabolites in the brain associated with the development of AD are present earlier than structural brain changes. The effect of sex on the metabolic profile during the development of AD has not yet been studied. In this study we longitudinally monitored and compared in vivo metabolic changes in male and female AβPPswe, PSEN1dE9 transgenic mice brains using magnetic resonance spectroscopy. Our results show a lower level of glutamate as well as of N-acetylaspartate (NAA) in transgenic mice. …The decline in NAA with age was more apparent in female mice. The level of taurine was higher in female mice and showed a faster decline over time. In conclusion, our study is the first to suggest that changes in the metabolic profile during AD development are influenced by sex. Show more

Keywords: Alzheimer's disease, AβPP/PS1 transgenic mouse model, longitudinal studies, magnetic resonance spectroscopy, sex differences

DOI: 10.3233/JAD-122188

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 1051-1059, 2013

Article Type: Other

DOI: 10.3233/JAD-122189

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 1061-1063, 2013

Article Type: Other

DOI: 10.3233/JAD-2013-34422

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 1065-1074, 2013