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