Journal of Alzheimer's Disease - Volume 40, issue 2

Authors: Rosen, Allyson C. | Ashford, John Wesson | Perry, George

Article Type: Review Article

Abstract: There are several points where ethical decision-making has become paralyzed and inefficient as the field of Alzheimer's disease study has advanced. The focus of this review is to highlight these points and several lines of research that can inform ethical decision-making. The goal is to identify barriers and to move toward solutions. Examples of other fields of study that can be particularly useful for innovative ways to study effective ethical decision-making include implementation science and neuroscience of decision-making, as well as therapeutic investigations of other domains such as the human biology and psychology.

DOI: 10.3233/JAD-132762

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 233-235, 2014

Authors: Krantic, Slavica | Torriglia, Alicia

Article Type: Review Article

Abstract: Alzheimer's disease (AD) develops undiagnosed for 10–15 years due to the lack of early diagnostic biomarkers. Visual deficits are common and crippling in AD patients and histopathological alterations found in the retina and brain are similar. We hypothesize that subtle morphological and functional changes in microglial and neuronal activities, such as those recently reported in the hippocampus, may also occur in retina during the preclinical stages of AD. These alterations are likely much more accessible to modern imaging and electrophysiological exploration than those occurring in the hippocampus and therefore, may serve as the earliest diagnostic biomarkers for AD.

Keywords: Alzheimer's disease, early biomarker, retina, synaptic activity, TNFα

DOI: 10.3233/JAD-132105

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 237-243, 2014

Authors: Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Mitochondria are essential cytoplasmic organelles, critical for cell survival and death. Recent mitochondrial research revealed that mitochondrial dynamics—the balance of fission and fusion in normal mitochondrial dynamics—is an important cellular mechanism in eukaryotic cell and is involved in the maintenance of mitochondrial morphology, structure, number, distribution, and function. Research into mitochondria and cell function has revealed that mitochondrial dynamics is impaired in a large number of aging and neurodegenerative diseases, and in several inherited mitochondrial diseases, and that this impairment involves excessive mitochondrial fission, resulting in mitochondrial structural changes and dysfunction, and cell damage. Attempts have been made to develop …molecules to reduce mitochondrial fission while maintaining normal mitochondrial fusion and function in those diseases that involve excessive mitochondrial fission. This review article discusses mechanisms of mitochondrial fission in normal and diseased states of mammalian cells and discusses research aimed at developing therapies, such as Mdivi, Dynasore and P110, to prevent or to inhibit excessive mitochondrial fission. Show more

Keywords: Alzheimer's disease, fission inhibitors, free radical production, mitochondrial dynamics, mitochondrial dysfunction, oxidative stress

DOI: 10.3233/JAD-132060

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 245-256, 2014

Authors: Gezen-Ak, Duygu | Yılmazer, Selma | Dursun, Erdinç

Article Type: Research Article

Abstract: Scientists have worked for over a century to uncover the basis of Alzheimer's disease (AD) with the ultimate goal of discovering a treatment. However, none of the approaches utilized have defined the exact cause of the disease or an ultimate treatment for AD. In this review, we aim to define the role of vitamin D in AD from a novel and fundamental perspective and attempt to answer the following question: Why should we seriously consider “simple” vitamin D as a “fundamental factor” in AD? To answer this question, we explain the protective effects of vitamin D in the central nervous …system and how the action of vitamin D and AD-type pathology overlap. Furthermore, we suggest that the role of vitamin D in AD includes not only vitamin D deficiency and vitamin D-related genes but also the disruption of vitamin D metabolism and action. This suggestion is supported by evidence that the disruption of vitamin D pathways mimic amyloid pathology. We define the term “inefficient utilization of vitamin D” as any alteration in vitamin D-related genes, including receptors, the enzymes related to vitamin D metabolism or the transporters of vitamin D, and we discuss the potential correlation of vitamin D status with the vulnerability of neurons to aging and neurodegeneration. Finally, in addition to the current knowledge that defines AD, we suggest that AD could be the result of a long-term hormonal imbalance in which the critical hormone is vitamin D, a secosteroid that has long been misnamed. Show more

Keywords: Alzheimer's disease, amyloid-β, calcium homeostasis, ERp57/1, 25-MARRS, haplotype, hormone imbalance, oxidative stress, VDR, vitamin D, vitamin D deficiency

DOI: 10.3233/JAD-131970

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 257-269, 2014

Authors: Ting, Simon Kang Seng | Benzinger, Tammie | Kepe, Vladimir | Fagan, Anne | Coppola, Giovanni | Porter, Verna | Hecimovic, Silva | Chakraverty, Suma | Alvarez-Retuerto, Ana Isabel | Goate, Alison | Ringman, John M.

Article Type: Short Communication

Abstract: Mutations in PSEN1 are the most common cause of autosomal dominant familial Alzheimer's disease (FAD). We describe an African-American woman with a family history consistent with FAD who began to experience cognitive decline at age 50. Her clinical presentation, MRI, FDG-PET, and PIB-PET scan findings were consistent with AD and she was found to have a novel I238M substitution in PSEN1. As this mutation caused increased production of Aβ42 in an in vitro assay, was not present in two population databases, and is conserved across species, it is likely to be pathogenic for FAD.

Keywords: African, Alzheimer's disease, amyloid-β42, autosomal dominant, familial, gamma-secretase, in vitro, PIB-PET, presenilin-1, PSEN1

DOI: 10.3233/JAD-131844

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 271-275, 2014

Authors: Shi, Zhongyong | Wu, Yujie | Wang, Meijuan | Cao, Jing | Feng, Wei | Cheng, Yan | Li, Chunbo | Shen, Yuan

Article Type: Research Article

Abstract: Thinning of retinal nerve fiber layer (RNFL) may reflect neurodegeneration of the central nervous system, which has been reported as part of the neuropathogenesis of Alzheimer's disease (AD). Specifically, AD patients have thinner RNFL as compared to age-matched normal controls. However, whether reduction of RNFL over time can predict those at higher risk to develop cognitive deterioration remains unknown. We therefore set out a prospective clinical investigation to determine both the reduction of RNFL thickness and the deterioration of cognitive function over a period of 25 months in 78 participants (mean age 72.31 ± 3.98 years, 52% men). The participants …were categorized as stable participants whose cognitive status remained unchanged (n = 60) and converted participants whose cognitive status deteriorated, which was diagnosed by DSM-VI (for AD) and Petersen's definition (for mild cognitive impairment) (n = 18). Here we show for the first time that the converted participants had greater reduction of RNFL thickness than the stable participants. Specifically, the reduction in the thickness of the inferior quadrant RNFL in the converted participants was greater than that in stable participants [−11.0 ± 12.8 (mean ± standard deviation) μm versus 0.4 ± 15.7 μm, p = 0.009]. These data showed that greater reduction in the inferior quadrant of RNFL thickness might indicate a higher risk for the old adults to develop cognitive deterioration. These findings have established a system to embark on a larger scale study to further test whether changes in RNFL thickness can serve as a biomarker of AD. Show more

Keywords: Alzheimer's disease, cognitive function, mild cognitive impairment, retinal nerve fiber layer thickness

DOI: 10.3233/JAD-131898

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 277-283, 2014

Authors: Cho, Hanna | Kim, Jeong-Hun | Kim, Changsoo | Ye, Byoung Seok | Kim, Hee Jin | Yoon, Cindy W. | Noh, Young | Kim, Geon Ha | Kim, Yeo Jin | Kim, Jung-Hyun | Kim, Chang-Hun | Kang, Sue J. | Chin, Juhee | Kim, Sung Tae | Lee, Kyung-Han | Na, Duk L. | Seong, Joon-Kyung | Seo, Sang Won

Article Type: Research Article

Abstract: Background: A large number of Alzheimer’s disease (AD) studies have focused on medial temporal and cortical atrophy, while changes in the basal ganglia or thalamus have received less attention. Objective: The aim of this study was to investigate the existence of progressive topographical shape changes in the basal ganglia (caudate nucleus, putamen, and globus pallidus) and thalamus concurrent with AD disease progression over three years. This study also examined whether declines in volumes of the basal ganglia or thalamus might be responsible for cognitive decline in patients with AD. Methods: Thirty-six patients with early stage AD …and 14 normal control subjects were prospectively recruited for this study. All subjects were assessed with neuropsychological tests and MRI at baseline and Years 1 and 3. A longitudinal shape analysis of the basal ganglia and thalamus was performed by employing a boundary surface-based shape analysis method. Results: AD patients exhibited specific regional atrophy in the right caudate nucleus and the bilateral putamen at baseline, and as the disease progressed, regional atrophic changes in the left caudate nucleus were found to conform to a distinct topography after controlling the total brain volume. Volumetric decline of the caudate nucleus and putamen correlated with cognitive decline in frontal function after controlling for age, gender, education, follow-up years, and total brain volume changes. Conclusion: Our findings suggest that shape changes of the basal ganglia occurred regardless of whole brain atrophy as AD progressed and were also responsible for cognitive decline that was observed from the frontal function tests. Show more

Keywords: Alzheimer's disease, basal ganglia, caudate nucleus, globus pallidus, putamen, shape, thalamus

DOI: 10.3233/JAD-132072

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 285-295, 2014

Authors: Xiong, Zhi | Thangavel, Ramasamy | Kempuraj, Duraisamy | Yang, Evert | Zaheer, Smita | Zaheer, Asgar

Article Type: Research Article

Abstract: Inflammatory responses are increasingly implicated in the pathogenesis of neurodegenerative diseases such as in Alzheimer's disease (AD). Interleukin-33 (IL-33), a member of IL-1 family, is constitutively expressed in the central nervous system and thought to be an important mediator of glial cell response to neuropathological lesions. Proinflammatory molecules are highly expressed at the vicinity of amyloid plaques (APs) and neurofibrillary tangles (NFTs), the hallmarks of AD pathology. We have investigated the expression of IL-33 and ST2 in relation to APs and NFTs in human AD and non-AD control brains by immunohistochemistry. Sections from the entorhinal cortex, where APs and NFTs …appear in early stages of AD, were used for immunohistochemistry. Mouse primary astrocytes were cultured and incubated with amyloid-β1-42 (Aβ1-42 ), component of plaque for 72 h and analyzed for the expression of IL-33 by flow cytometry. We found strong expression of IL-33 and ST2 in the vicinity of Aβ and AT8 labelled APs and NFTs respectively, and in the glial cells in AD brains when compared to non-AD control brains. IL-33 and ST2 positive cells were also significantly increased in AD brains when compared to non-AD brains. Flow cytometric analysis revealed incubation of mouse astrocytes with Aβ1-42 increased astrocytic IL-33 expression in vitro. These results suggest that IL-33, an alamin cytokine, may induce inflammatory molecule release from the glial cells and may play an important role in the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, amyloid plaques, glia maturation factor, IL-33, neurofibrillary tangles, ST2

DOI: 10.3233/JAD-132081

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 297-308, 2014

Authors: Savage, Sharon A. | Piguet, Olivier | Hodges, John R.

Article Type: Research Article

Abstract: Background: Anomia is a common and debilitating symptom for many dementia sufferers, but is particularly marked in patients with the semantic variant of primary progressive aphasia, semantic dementia (SD). Recent studies have demonstrated that through cognitive training these patients can re-learn the names of objects, but it remains unclear whether this translates to improved use of these relearned words in contexts other than picture naming. Methods: Five SD patients completed a 2-month, online word training program and were assessed pre- and post-intervention on picture naming and spoken word-picture-matching plus two novel ecological tasks: video description and responses to …verbal requests. Results: All participants showed clear gains in naming the trained pictures (p < 0.001). Importantly, improvements were also observed for four out of the five patients on the video description task. Milder patients also demonstrated improved comprehension of verbal instructions. Severe SD patients showed improvements on matching trained words to pictures. As expected, improvements were not found for untrained items. Conclusion: There was clear evidence of generalization especially in patients with milder semantic impairments. Future studies should investigate the utility of this training in other forms of dementia. Show more

Keywords: computer-assisted intervention, cognitive rehabilitation, generalization, naming therapy, primary progressive aphasia, semantic dementia

DOI: 10.3233/JAD-131826

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 309-317, 2014

Authors: Rice, Ann C. | Keeney, Paula M. | Algarzae, Norah K. | Ladd, Amy C. | Thomas, Ravindar R. | Bennett Jr., James P.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers …compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aβ1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment Aβ25-35 , mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD. Show more

Keywords: Laser capture microdissection, neural stem cells, PGC1 alpha, real-time PCR, TFAM

DOI: 10.3233/JAD-131715

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 319-330, 2014

Authors: Wharton, Whitney | Gleason, Carey E. | Dowling, N. Maritza | Carlsson, Cynthia M. | Brinton, Eliot A. | Santoro, M. Nanette | Neal-Perry, Genevieve | Taylor, Hugh | Naftolin, Frederick | Lobo, Rogerio A. | Merriam, George | Manson, JoAnn E. | Cedars, Marcelle I. | Miller, Virginia M. | Black, Dennis M. | Budoff, Matthew | Hodis, Howard N. | Harman, S. Mitchell | Asthana, Sanjay

Article Type: Research Article

Abstract: Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition. …All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42–59 years), healthy, and free of cognitive dysfunction. Higher systolic BP was weakly related to poorer performance in auditory working memory and attention (p = 0.004; adjusted for multiple comparisons p = 0.10). This relationship was not associated with endogenous hormone levels, and systolic BP was not related to any other cognitive domain. BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy, recently menopausal women. Lower BP early in menopause may affect cognitive domains known to be associated with AD. Show more

Keywords: Attention, blood pressure, clinical trial, cognition, estradiol, estrogen, hormone therapy, memory, vascular risk

DOI: 10.3233/JAD-130245

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 331-341, 2014

Authors: Nielsen, Henrietta M. | Hall, Sara | Surova, Yulia | Nägga, Katarina | Nilsson, Christer | Londos, Elisabet | Minthon, Lennart | Hansson, Oskar | Wennström, Malin

Article Type: Research Article

Abstract: The proteoglycan NG2 plays a major role in proliferation, migration, and differentiation of pericytes and NG2 cells in the brain. We have previously reported decreased soluble NG2 (sNG2) levels in cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) and a relationship between sNG2 and AD biomarkers in these patients. To further investigate whether alterations in sNG2 is specific to AD pathology, we measured levels of sNG2 in CSF from a patient cohort consisting of non-demented controls (n = 51), patients with Parkinson's disease (PD) (n = 61), and patients with dementia with Lewy bodies (DLB) (n = 37), two …synucleinopathies whereof the latter disorder frequently coincides with amyloid-β pathology similar to AD. We found decreased sNG2 concentrations in DLB patients, but not in PD patients, compared to controls. Levels of sNG2 in controls and PD patients correlated to T-tau, P-tau, α-synuclein, and neurosin. Only one correlation, between sNG2 and neurosin, was found in DLB patients. Analysis of a second cohort consisting of controls (n = 23) and DLB patients (n = 31) showed that the result was reproducible, as lower levels of sNG2 again were found in DLB patients compared to controls. We conclude that lower levels of sNG2 levels indicate a DLB-related impact on NG2 expressing cells foremost associated with neuropathology linked to accumulation of amyloid-β and not α-synuclein. Show more

Keywords: α-synuclein, Alzheimer's disease markers, amyloid-β, biomarker, cerebrospinal fluid, dementia with Lewy bodies, NG2, neurosin, Parkinson's disease, synucleinopathies

DOI: 10.3233/JAD-132246

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 343-350, 2014

Authors: Mroczko, Barbara | Groblewska, Magdalena | Zboch, Marzena | Kulczyńska, Agnieszka | Koper, Olga M. | Szmitkowski, Maciej | Kornhuber, Johannes | Lewczuk, Piotr

Article Type: Research Article

Abstract: Background: A growing body of evidence shows the involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in neurodegeneration processes, but reports of their concentrations in the cerebrospinal fluid (CSF) are inconsistent. Objective: Therefore, the aim of our study was to evaluate the CSF concentrations of MMP-2, MMP-3, MMP-9, and their inhibitors (TIMP-1 and TIMP-2) in carefully selected groups of patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and non-demented controls, whose clinical and neuropsychological diagnoses were confirmed by the corresponding CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio, …and increased concentrations of Tau and pTau181 proteins. Methods: The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of MMPs and TIMPs were determined with ELISAs. Results: CSF concentrations of MMP-9 were significantly lower, and the concentrations of MMP-3 significantly higher in AD patients compared to the controls. Neither MMP-2 nor TIMPs showed significant changes among the groups investigated. Conclusion: Altered concentrations of two out of three MMPs investigated in this study suggest that this family of biomolecules may play a role in the AD pathophysiology. Further studies are needed to establish their potential diagnostic utility. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases

DOI: 10.3233/JAD-131634

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 351-357, 2014

Authors: Gray, Nora E. | Morré, Jeff | Kelley, Jeremiah | Maier, Claudia S. | Stevens, Jan F. | Quinn, Joseph F. | Soumyanath, Amala

Article Type: Research Article

Abstract: The accumulation of amyloid-β (Aβ) is a hallmark of Alzheimer's disease and is known to result in neurotoxicity both in vivo and in vitro. We previously demonstrated that treatment with the water extract of Centella asiatica (CAW) improves learning and memory deficits in Tg2576 mice, an animal model of Aβ accumulation. However the active compounds in CAW remain unknown. Here we used two in vitro models of Aβ toxicity to confirm this neuroprotective effect and identify several active constituents of the CAW extract. CAW reduced Aβ-induced cell death and attenuated Aβ-induced changes in tau expression and phosphorylation in both the …MC65 and SH-SY5Y neuroblastoma cell lines. We confirmed and quantified the presence of several mono- and dicaffeoylquinic acids (CQAs) in CAW using chromatographic separation coupled to mass spectrometry and ultraviolet spectroscopy. Multiple dicaffeoylquinic acids showed efficacy in protecting MC65 cells against Aβ-induced cytotoxicity. Isochlorogenic acid A and 1,5-dicaffeoylquinic acid were found to be the most abundant CQAs in CAW, and the most active in protecting MC65 cells from Aβ-induced cell death. Both compounds showed neuroprotective activity in MC65 and SH-SY5Y cells at concentrations comparable to their levels in CAW. Each compound not only mitigated Aβ-induced cell death, but was able to attenuate Aβ-induced alterations in tau expression and phosphorylation in both cell lines, as seen with CAW. These data suggest that CQAs are active neuroprotective components in CAW, and therefore are important markers for future studies on CAW standardization, bioavailability, and dosing. Show more

Keywords: Amyloid-β toxicity, caffeoylquinic acids, Centella asiatica, neuroprotection, tau

DOI: 10.3233/JAD-131913

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 359-373, 2014

Authors: García-Casares, Natalia | Berthier, Marcelo L. | Jorge, Ricardo E. | Gonzalez-Alegre, Pedro | Gutiérrez Cardo, Antonio | Rioja Villodres, José | Acion, Laura | Ariza Corbo, María José | Nabrozidis, Alejandro | García-Arnés, Juan A. | González-Santos, Pedro

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) is an emerging risk factor for cognitive impairment. Whether this impairment is a direct effect of this metabolic disorder on brain function, a consequence of vascular disease, or both, remains unknown. Structural and functional neuroimaging studies in patients with T2DM could help to elucidate this question. Objective: We designed a cross-sectional study comparing 25 T2DM patients with 25 age- and gender-matched healthy control participants. Clinical information, APOE genotype, lipid and glucose analysis, structural cerebral magnetic resonance imaging including voxel-based morphometry, and F-18 fluorodeoxyglucose positron emission tomography were obtained in all subjects. …Methods: Gray matter densities and metabolic differences between groups were analyzed using statistical parametric mapping. In addition to comparing the neuroimaging profiles of both groups, we correlated neuroimaging findings with HbA1c levels, duration of T2DM, and insulin resistance measurement (HOMA-IR) in the diabetic patients group. Results: Patients with T2DM presented reduced gray matter densities and reduced cerebral glucose metabolism in several fronto-temporal brain regions after controlling for various vascular risk factors. Furthermore, within the T2DM group, longer disease duration, and higher HbA1c levels and HOMA-IR were associated with lower gray matter density and reduced cerebral glucose metabolism in fronto-temporal regions. Conclusion: In agreement with previous reports, our findings indicate that T2DM leads to structural and metabolic abnormalities in fronto-temporal areas. Furthermore, they suggest that these abnormalities are not entirely explained by the role of T2DM as a cardiovascular risk factor. Show more

Keywords: cognition, magnetic resonance imaging, neuroimaging, positron emission tomography, type 2 diabetes mellitus

DOI: 10.3233/JAD-131736

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 375-386, 2014

Authors: Liu, Xuena | Wang, Siqi | Zhang, Xinqing | Wang, Zhiqun | Tian, Xiaojie | He, Yong

Article Type: Research Article

Abstract: We used resting-state functional magnetic resonance imaging to measure the amplitude of low-frequency fluctuations (ALFF) of intrinsic brain activity in 23 patients with moderate Alzheimer's disease (AD) and 27 age- and gender-matched healthy controls. Two different frequency bands were analyzed (slow-5:0.01–0.027 Hz; slow-4:0.027–0.073 Hz). In many brain regions, widespread ALFF differences between the two frequency bands were observed, including predominantly the posterior cingulate cortex/precuneus (PCC/PCu), hippocampus/parahippocampal gyrus (Hip/PHG), insula, thalamus, and basal ganglia. Compared to controls, AD patients showed decreased ALFF values in the bilateral PCC/PCu, inferior parietal lobe, and several temporal regions, and increased ALFF values mainly in the …bilateral Hip/PHG, and middle and inferior temporal gyri. Intriguingly, the ALFF abnormalities in the left PCu, left supramarginal gyrus, and several temporal regions were greater in the slow-5 band compared to the slow-4 band. Moreover, correcting for gray matter volume loss significantly affected the functional analytical results, suggesting that gray matter loss can partially account for the functional imaging analytical results obtained in AD. Finally, we showed that regions with changes in ALFF demonstrated a significant correlation with patient cognitive performance as measured using Mini-Mental State Examination scores. The results also demonstrated a significant correlation between hippocampal volume and the ALFF in slow-5 band in the AD group. This study demonstrated widespread ALFF abnormalities of intrinsic brain activity in AD and revealed that the ALFF abnormalities in severe specific regions were frequency-dependent. Taken together, our findings provided novel insights into the pathophysiological mechanism of AD and may be helpful in the development of imaging biomarkers for disease diagnosis. Show more

Keywords: Alzheimer's disease, amplitude of low-frequency fluctuation, intrinsic brain activity, resting-state functional magnetic resonance imaging

DOI: 10.3233/JAD-131322

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 387-397, 2014

Authors: Dias, Irundika H.K. | Polidori, Maria Cristina | Li, Li | Weber, Daniela | Stahl, Wilhelm | Nelles, Gereon | Grune, Tilman | Griffiths, Helen R.

Article Type: Research Article

Abstract: Elevated serum cholesterol concentrations in mid-life increase risk for Alzheimer's disease (AD) in later life. However, lower concentrations of cholesterol-carrying high density lipoprotein (HDL) and its principal apolipoprotein A1 (ApoA1) correlate with increased risk for AD. As HDL transports oxocarotenoids, which are scavengers of peroxynitrite, we have investigated the hypothesis that lower HDL and oxocarotenoid concentrations during AD may render HDL susceptible to nitration and oxidation and in turn reduce the efficiency of reverse cholesterol transport (RCT) from lipid-laden cells. Fasting blood samples were obtained from subjects with 1) AD without cardiovascular comorbidities and risk factors (AD); 2) AD with …cardiovascular comorbidities and risk factors (AD Plus); 3) normal cognitive function; for carotenoid determination by HPLC, analysis of HDL nitration and oxidation by ELISA, and 3 H-cholesterol export to isolated HDL. HDL concentration in the plasma from AD Plus patients was significantly lower compared to AD or control subject HDL levels. Similarly, lutein, lycopene, and zeaxanthin concentrations were significantly lower in AD Plus patients compared to those in control subjects or AD patients, and oxocarotenoid concentrations correlated with Mini-Mental State Examination scores. At equivalent concentrations of ApoA1, HDL isolated from all subjects irrespective of diagnosis was equally effective at mediating RCT. HDL concentration is lower in AD Plus patients' plasma and thus capacity for RCT is compromised. In contrast, HDL from patients with AD-only was not different in concentration, modifications, or function from HDL of healthy age-matched donors. The relative importance of elevating HDL alone compared with elevating carotenoids alone or elevating both to reduce risk for dementia should be investigated in patients with early signs of dementia. Show more

Keywords: Aging, Alzheimer's disease, free radical scavenger, 3-nitrotyrosine, protein carbonyl formation, protein oxidation

DOI: 10.3233/JAD-131964

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 399-408, 2014

Authors: Schmand, Ben | Rienstra, Anne | Tamminga, Hyke | Richard, Edo | van Gool, Willem A. | Caan, Matthan W.A. | Majoie, Charles B.

Article Type: Research Article

Abstract: Background: Scales of global cognition and behavior, often used as endpoints for intervention trials in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), are insufficiently responsive (i.e., relatively insensitive to change). Large patient samples are needed to detect beneficial drug effects. Therefore, magnetic resonance imaging (MRI) measures of cerebral atrophy have been proposed as surrogate endpoints. Objective: To examine how neuropsychological assessment compares to MRI in this respect. Methods: We measured hippocampal atrophy, cortical thickness, and performance on neuropsychological tests in memory clinic patients at baseline and after two years. Neurologists rated the patients as cognitively …normal (n = 28; Clinical Dementia Rating, CDR = 0) or as impaired (n = 34; CDR > 0). We administered five tests of memory, executive functioning, and verbal fluency. A composite neuropsychological score was calculated by taking the mean of the demographically corrected standard scores. MRI was done on a 3 Tesla scanner. Volumetric measurements of the hippocampus and surrounding cortex were made automatically using FreeSurfer software. Results: The composite neuropsychological score deteriorated 0.6 SD in the impaired group, and was virtually unchanged in the normal group. Annual hippocampal atrophy rates were 3.4% and 0.6% in the impaired and normal cognition groups, respectively. Estimates of required sample sizes to detect a 50% reduction in rate of change were larger using rate of hippocampal atrophy (n = 131) or cortical thickness (n = 488) as outcome compared to change scores on neuropsychological assessment (n = 62). Conclusion: Neuropsychological assessment is more responsive than MRI measures of brain atrophy for detecting disease progression in memory clinic patients with MCI or AD. Show more

Keywords: Alzheimer's disease, cognition, hippocampus, longitudinal design, magnetic resonance imaging, mild cognitive impairment, neuropsychological tests, responsiveness

DOI: 10.3233/JAD-131484

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 409-418, 2014

Authors: Liu, Xinghua | Wang, Zhihong | Xia, Yiyuan | Yu, Guang | Zeng, Kuan | Luo, Hongbin | Hu, Jichang | Gong, Cheng-Xin | Wang, Jian-Zhi | Zhou, Xin-Wen | Wang, Xiao-Chuan

Article Type: Research Article

Abstract: Recent studies have reported a correlation between dementia and low blood pressure. How hypotension is associated with the increased risk of Alzheimer's disease (AD) remains unclear. Here we show that one month treatment of losartan, an angiotensin II type 1 (AT1) receptor antagonist, causes chronic and sustained hypotension, along with oxidative stress in adult male Sprague-Dawley rats. Furthermore, we show that losartan treatment increases the level of inactivated protein phosphatase 2A (PP2A) and the hyperphosphorylation of tau at Ser 199 and Ser 396. Rats treated with losartan present memory deficits and decreases in spine-density. These findings suggest that losartan-induced hypotension …may increase the risk of AD-like pathological alteration and behavioral impairment through oxidative stress which leads to tau hyperphosphorylation and loss of dendritic spines. Show more

Keywords: Alzheimer's disease, hypotension, losartan, memory deficit, oxidative stress, tau hyperphosphorylation

DOI: 10.3233/JAD-131679

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 419-427, 2014

Authors: Dalby, Nils Ole | Volbracht, Christiane | Helboe, Lone | Larsen, Peter Hjørringaard | Jensen, Henrik Sindal | Egebjerg, Jan | Elvang, Anders Brandt

Article Type: Research Article

Abstract: The formation of neurofibrillary tangles from the assembly of hyperphosphorylated tau leads to dendritic and axonal instability, synaptic degeneration, and neuronal loss. To understand the early physiological consequences of aberrant tau expression, we characterized the physiology of CA1 pyramidal neurons in rTg4510 female mice and non-transgenic (wt) littermate controls. We studied mice at the age of 10–12 weeks where only minimal hyperphosphorylated pretangle tau was present, and 22–24 weeks old mice with significant neurofibrillary tangle pathology. Our electrophysiological analysis included input–output relation, paired-pulse facilitation, and whole cell patch-clamp recordings of neurons to measure action potential threshold and action potential properties, …chord-conductance, and characterization of AMPA receptor mediated synaptic transmission. We found that the input–output relation in field (excitatory postsynaptic potentials, EPSP) and whole cell recordings (excitatory postsynaptic currents, EPSC) were impaired in rTg4510 mice compared to wt controls at both ages. We measured a diminished tail current charge after depolarizing voltage input in rTg4510 mice compared to wt in both young and aged mice. Additionally, mini-EPSC properties (peak and decay time) were essentially similar between genotypes and age groups investigated. Surprisingly, in the 22–24 week old group, the mini-EPSC frequency was significantly increased (interevent interval 0.8 ± 0.1 in wt compared to 0.3 ± 0.1 in rTg4510 mice). These data indicate that the developmentally regulated expression of human P301L tau in CA1 pyramidal neurons coincide with changes in neuronal excitability but also that significant presynaptic changes occur late during the progression of tau pathology in this mouse model. Show more

Keywords: CA1, excitatory postsynaptic currents, hippocampus, postsynaptic, presynaptic, readily releasable pool, rTg4510 model, tauopathy

DOI: 10.3233/JAD-131358

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 429-442, 2014

Authors: Rosa, Maria Inês | Perucchi, Josmar | Medeiros, Lidia Rosi | Fernandes, Bruna | Fernandes dos Reis, Maria Eduarda | Silva, Bruno Rosa

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 65–70% of all dementia cases. Objective: We performed a systematic review and meta-analysis to estimate the accuracy of cerebrospinal fluid Aβ1-42 for the diagnosis of AD. A comprehensive search of the Cochrane Library, MEDLINE, LILACS, Grey literature, and EMBASE was performed for papers published from January 1990 to August 2013. The following Medical Subject Headings (MeSH) terms were searched: “Alzheimer disease” or “AD” and “amyloid-β” or “Aβ1-42 ”. Methods: We included case-control and cross-sectional studies, prospective or retrospective, that evaluated Aβ1-42 …levels in AD. Statistical analysis was performed using REVMAN 5.2, Meta Disc, and Stata 11.0. Results: A total of 804 citations were identified by the search strategy and 41 studies were included. Meta-analysis showed a sensitivity of 84.3% (95% CI: 85.6%–81%) and specificity of 79.4% (95% CI: 77.6%–81.1%). The diagnostic odds ratio was 28.9 (95% CI: 21.2–39.5). Conclusion: Our study demonstrated that Aβ1-42 can discriminate AD from controls with good sensitivity and specificity. Show more

Keywords: Aβ1-42, Alzheimer's disease, meta-analyses, systematic review

DOI: 10.3233/JAD-132264

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 443-454, 2014

Authors: Boccia, Maddalena | Silveri, Maria Caterina | Guariglia, Cecilia

Article Type: Research Article

Abstract: In the past two decades research has highlighted how implicit memory processes are spared in degenerative disorders, such as Alzheimer's disease (AD), which are characterized by the early onset of explicit memory deficits. However, according to recent studies, there may be dissociations among different types of implicit memory. Although several studies have shown selective sparing of lexical priming in AD, it is not completely clear what happens to other types of implicit memory processes, such as visuo-perceptual priming. The present study examines the possibility that the visuo-perceptual priming effect is spared in AD. We tested two groups of participants, i.e., …a group of AD patients and a group of healthy age-matched controls, using a visuo-perceptual priming task. The task required the identification of fragmented pictures. Results showed a deficient priming effect in AD patients when it was measured by an Identification of Fragmented Pictures task. We discuss our results in light of the current hypothesis of a functional segregation in priming processes. Show more

Keywords: Alzheimer's disease, implicit memory, neuropsychology, normal aging, visuo-perceptive priming

DOI: 10.3233/JAD-131775

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 455-463, 2014

Authors: Romero, Juan Pablo | Benito-León, Julián | Louis, Elan D. | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: Previous studies have shown that Alzheimer's disease (AD) is associated with a reduced risk of cancer. However, most studies exclude those with undiagnosed dementia. The only way to overcome this methodological issue is to examine all the participants or to screen the population for symptoms of dementia with a validated instrument and confirm any suspected dementia patients with a clinical examination (i.e., a two-phase investigation method). We used this methodology to estimate whether cancer-specific mortality is associated with AD and other types of dementia in a prospective population-based study (NEDICES) involving 5,278 elderly people. Community-dwelling subjects with and without dementia …were identified and followed for a median of 12.5 years, after which the death certificates of those who deceased were examined. A total of 1,976 (47.1%) died, including 277 who had possible or probable AD and 126 with non-AD dementia. Cancer was reported significantly less often in those with possible or probable AD (5.8%) or non-AD dementia (6.3%) than in those without dementia (26.5%). In an unadjusted Cox model, hazard ratio (HR) of cancer-specific mortality in participants with AD = 0.45 (p = 0.002) and HR in participants with non-AD dementia = 0.62 (p = 0.179) when compared to the non-demented group. In a Cox model that adjusted for a variety of demographic factors and co-morbidities, HRs of cancer-specific mortality in participants with AD = 0.50 (p = 0.028) and 0.97 (p = 0.942) in non-AD dementia. This study provides further evidence of an inverse association between cancer and AD. Show more

Keywords: Cancer, death certificates, dementia, elderly, epidemiology, population-based study

DOI: 10.3233/JAD-132048

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 465-473, 2014

Article Type: Correction

Abstract: Erratum to: Journal of Alzheimer's Disease 38(4), 2014, 857-866, DOI 10.3233/JAD-13121

DOI: 10.3233/JAD-149001

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 475-475, 2014

Article Type: Other

DOI: 10.3233/JAD-132049

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 477-479, 2014