Journal of Alzheimer's Disease - Volume 51, issue 3

Authors: Adam, Pavlína | Křížková, Soňa | Heger, Zbyněk | Babula, Petr | Pekařík, Vladimír | Vaculovičoá, Markéta | Gomes, Cláudio M. | Kizek, René | Adam, Vojtěch

Article Type: Review Article

Abstract: Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and the low …molecular mass thiol-rich metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with the relationship between metallothionein isoforms and metal ion regulation of their homeostasis. Show more

Keywords: Alzheimer’s disease, brain, copper, metallothionein, neurodegenerative disorders, prion protein

DOI: 10.3233/JAD-150984

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 637-656, 2016

Authors: Southam, Katherine A. | Vincent, Adele J. | Small, David H.

Article Type: Research Article

Abstract: Although the cause of Alzheimer’s disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain’s immune cells. They play an important role in maintaining the brain’s extracellular environment, including clearance of aggregated proteins such as amyloid-β (Aβ). Recent studies suggest that microglia play a more active role in the brain than initially considered. Specifically, microglia provide …trophic support to neurons and also regulate synapses. Microglial regulation of neuronal activity may have important consequences for AD. In this article we review the function of microglia in AD and examine the possible relationship between microglial dysfunction and network abnormalities, which occur very early in disease pathogenesis. Show more

Keywords: Microglia, network abnormalities, neural networks, phagocytosis, synapse pruning

DOI: 10.3233/JAD-151075

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 657-669, 2016

Authors: Lyoo, Chul Hyoung | Cho, Hanna | Choi, Jae Yong | Hwang, Mi Song | Hong, Sang Kyoon | Kim, Yun Joong | Ryu, Young Hoon | Lee, Myung Sik

Article Type: Short Communication

Abstract: We studied topographic distribution of tau and amyloid-β in a patient with variant Alzheimer’s disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-β in the primary motor cortex.

Keywords: Alzheimer’s disease, amyloid, PET, spastic paraplegia, tau protein

DOI: 10.3233/JAD-151052

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 671-675, 2016

Authors: Sierksma, Annerieke S.R. | de Nijs, Laurence | Hoogland, Govert | Vanmierlo, Tim | van Leeuwen, Fred W. | Rutten, Bart P.F. | Steinbusch, Harry W.M. | Prickaerts, Jos | van den Hove, Daniel L.A.

Article Type: Short Communication

Abstract: Treatment of Alzheimer’s disease (AD) patients with the antidepressant fluoxetine is known to improve memory and cognitive function. However, the mechanisms underlying these effects are largely unknown. To unravel these mechanisms, we aimed to treat APPswe/PS1dE9 mice with fluoxetine. Unexpectedly, with time, an increased number of animals displayed seizure behavior and died. Although spontaneous behavioral seizures have been reported previously in this mouse model, the observation of seizures and death consequential to fluoxetine treatment is new. Our results warrant further research on the underlying mechanisms as this may refine the treatment of AD patients.

Keywords: Alzheimer’s disease, APPswe/PS1dE9, epilepsy, fluoxetine, premature death, seizure

DOI: 10.3233/JAD-151066

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 677-682, 2016

Authors: Stoeck, Katharina | Psychogios, Marios Nikos | Ohlenbusch, Andreas | Steinfeld, Robert | Schmidt, Jens

Article Type: Research Article

Abstract: A 48-year-old male patient presented with personality changes and progressive memory loss over 2 years with initially suspected Hashimoto’s encephalopathy. Strategy of diagnostic workup of early onset dementia included dementia from neurodegenerative, neuroinflammatory, metabolic/toxic, and psychiatric origin. The patient’s neurological exam was normal. MRI revealed a leukencephalopathy, predominantly in the frontal periventricular white matter, without notable changes over 2 years. On neurophysiological examination, prolonged central conduction times and a sensorimotor polyneuropathy were noted. Neuropsychological impairment included disorientation in place and a reduced short time memory. Behavioral alterations were predominated by sudden mood changes and disinhibition. Cerebrospinal fluid was normal. Despite …presence of thyroid autoantibodies, glucocorticosteroid treatment did not improve the dementia. A metachromatic leukodystrophy was diagnosed by decreased arylsulfatase-A activity in leucocytes/fibroblasts and identification of a compound heterozygous mutation in the ARSA gene: c.542T>G (exon 3) and the novel mutation c.1013T>C (exon 6). Pathogenic function was suggested by bioinformatic mutation search. In a patient with early onset dementia, strategic diagnostic workup including genetic assessment revealed an adult-onset metachromatic leukodystrophy with a novel mutation in the arylsulfatase A gene. Show more

Keywords: Arylsulfatase A, early onset dementia, genetic testing, late-onset metachromatic leukodystrophy

DOI: 10.3233/JAD-150819

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 683-687, 2016

Authors: Peters, Christian | Bascuñán, Denisse | Opazo, Carlos | Aguayo, Luis G.

Article Type: Research Article

Abstract: A major characteristic of Alzheimer’s disease (AD) is the presence of amyloid-β peptide (Aβ) oligomers and aggregates in the brain. It is known that Aβ oligomers interact with the neuronal membrane and induce perforations that cause an influx of calcium ions and enhance the release of synaptic vesicles leading to a delayed synaptic failure by vesicle depletion. To better understand the mechanism by which Aβ exerts its effect on the plasma membrane, we evaluated three Aβ fragments derived from different regions of Aβ1 - 42 ; Aβ1 - 28 from the N-terminal region, Aβ25 - 35 from the central region, and Aβ17 - 42 from …the C-terminal region. The neuronal activities of these fragments were examined with patch clamp, immunofluorescence, transmission electron microscopy, aggregation assays, calcium imaging, and MTT reduction assays. The present results indicate that the fragment Aβ1 - 28 contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; Aβ25 - 35 is important for membrane perforation, calcium increase, and synaptotoxicity; and Aβ17 - 42 induced mitochondrial toxicity similar to the full length Aβ1 - 42 , but was unable to induce membrane perforation and calcium increase, supporting the idea that it is less toxic in the non-amyloidogenic pathway. Show more

Keywords: Alzheimer’s disease, amyloid, membranes, peptides, pore

DOI: 10.3233/JAD-150896

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 689-699, 2016

Authors: Bonet-Costa, Vicent | Herranz-Pérez, Vicente | Blanco-Gandía, MariCarmen | Mas-Bargues, Cristina | Inglés, Marta | Garcia-Tarraga, Patricia | Rodriguez-Arias, Marta | Miñarro, Jose | Borras, Consuelo | Garcia-Verdugo, Jose Manuel | Viña, Jose

Article Type: Research Article

Abstract: Amyloid-β (Aβ) clearance from brain, which is decreased in Alzheimer’s disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPARγ dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPARγ . Treatment of an Alzheimer’s disease mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit memory, and odor discrimination. This is associated with a lowering of Aβ levels in brain, in the number and the area of amyloid …plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Finally, incubation of primary astrocytes with genistein results in a PPARγ -mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer’s disease. Show more

Keywords: Aging, biomedical research, neurodegenerative disease, neuroscience, phytoestrogens

DOI: 10.3233/JAD-151020

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 701-711, 2016

Authors: Külzow, Nadine | Witte, A. Veronica | Kerti, Lucia | Grittner, Ulrike | Schuchardt, Jan Philipp | Hahn, Andreas | Flöel, Agnes

Article Type: Research Article

Abstract: As the process of Alzheimer’s disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning …and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50–75 years received either LC-n3-FA (2,200 mg/day, n  = 22) or placebo (n  = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age. Show more

Keywords: Cognitive aging, dietary prevention, docosahexaenoic acid, eicosapentaenoic acid, fish oil

DOI: 10.3233/JAD-150886

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 713-725, 2016

Authors: LoBue, Christian | Denney, David | Hynan, Linda S. | Rossetti, Heidi C. | Lacritz, Laura H. | Hart Jr., John | Womack, Kyle B. | Woon, Fu L. | Cullum, C. Munro

Article Type: Research Article

Abstract: This study examined whether history of traumatic brain injury (TBI) is associated with increased risk and earlier onset of mild cognitive impairment (MCI). Subjects with MCI (n  = 3,187) and normal cognition (n  = 3,244) were obtained from the National Alzheimer’s Coordinating Center database. TBI was categorized based on lifetime reported TBI with loss of consciousness (LOC) without chronic deficit. Logistic regression was used to examine TBI history as a predictor of MCI, adjusted for demographics, apolipoprotein E-ɛ 4 (ApoE4), a composite vascular risk score, and history of psychiatric factors. ANCOVA was used to examine whether age at MCI diagnosis and estimated …age of onset differed between those with (TBI+) and without (TBI–) a history of TBI. TBI history was a significant predictor (p  <  0.01) and associated with increased odds of MCI diagnosis in unadjusted (OR = 1.25; 95% CI = 1.05–1.49) and adjusted models, accounting for age, education, ApoE4, and a composite vascular score (OR = 1.32; 95% CI = 1.10–1.58). This association, however, was largely attenuated (OR = 1.14; 95% CI = 0.94–1.37; p  = 0.18) after adjustment for reported history of depression. MCI was diagnosed a mean of 2.3 years earlier (p  <  0.001) in the TBI+ group, and although TBI+ subjects had an estimated mean of decline 1.7 years earlier, clinician-estimated age of onset failed to differ (p  = 0.13) when gender and psychiatric factors were controlled. This is the first report of a possible role for TBI as a risk factor in MCI, but its association may be related to other factors such as gender and depression and requires further investigation. Show more

Keywords: Age of onset, mild cognitive impairment, risk factors, traumatic brain injury

DOI: 10.3233/JAD-150895

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 727-736, 2016

Authors: Moon, Yeonsil | Han, Seol-Heui | Moon, Won-Jin

Article Type: Research Article

Abstract: Background: Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer’s disease (AD) are rarely investigated. Objective: To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM). Materials and Methods: Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this institutional review-board approved study. Susceptibility maps were reconstructed from a three-dimensional multiecho spoiled gradient-echo sequence. …Four regions of interest were drawn manually on QSM images, namely the globus pallidus, putamen, caudate nucleus, and pulvinar nucleus of the thalamus. Comparisons of patient demographics, and iron concentrations among the VaD, AD, and control subjects were assessed using analysis of variance and post-hoc analyses. The relationships of age and cognitive state with susceptibility values were assessed using partial correlation analysis. Results: In VaD and AD, overall susceptibility values were higher than those of control subjects. A significant difference in susceptibility values was found in the putamen and caudate nucleus (p  <  0.001 and p  = 0.002, respectively). However, susceptibility values did not differ between VaD and AD. Age and cognitive deficit severity were not related to susceptibility values in the VaD and AD groups. Conclusion: Increased iron deposition in the putamen and caudate nucleus in VaD and AD patients was not associated with age or the severity of cognitive deficits. Further evaluations are needed to determine the temporal changes in iron load and their diagnostic role in dementia pathology. Show more

Keywords: Cognitive decline, imaging, iron

DOI: 10.3233/JAD-151037

Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 737-745, 2016