Journal of Alzheimer's Disease - Volume 59, issue 4

Authors: Skogseth, Ragnhild | Hortobágyi, Tibor | Soennesyn, Hogne | Chwiszczuk, Luiza | Ffytche, Dominic | Rongve, Arvid | Ballard, Clive | Aarsland, Dag

Article Type: Research Article

Abstract: Background: The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally. Objective: To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson’s disease with dementia (PDD). Methods: From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had …mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB. Results: 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n  = 11), PDD (n  = 5), probable (n  = 2) or possible (n  = 2) Alzheimer’s disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%. Conclusion: Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy. Show more

Keywords: Autopsy, dementia, diagnosis, Lewy body disease, neuropathology, Parkinson’s disease

DOI: 10.3233/JAD-170274

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1139-1152, 2017

Authors: Iyappan, Anandhi | Younesi, Erfan | Redolfi, Alberto | Vrooman, Henri | Khanna, Shashank | Frisoni, Giovanni B. | Hofmann-Apitius, Martin | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Ontologies and terminologies are used for interoperability of knowledge and data in a standard manner among interdisciplinary research groups. Existing imaging ontologies capture general aspects of the imaging domain as a whole such as methodological concepts or calibrations of imaging instruments. However, none of the existing ontologies covers the diagnostic features measured by imaging technologies in the context of neurodegenerative diseases. Therefore, the Neuro-Imaging Feature Terminology (NIFT) was developed to organize the knowledge domain of measured brain features in association with neurodegenerative diseases by imaging technologies. The purpose is to identify quantitative imaging biomarkers that can be extracted from multi-modal …brain imaging data. This terminology attempts to cover measured features and parameters in brain scans relevant to disease progression. In this paper, we demonstrate the systematic retrieval of measured indices from literature and how the extracted knowledge can be further used for disease modeling that integrates neuroimaging features with molecular processes. Show more

Keywords: Alzheimer’s disease, annotation, brain, neuroimaging, terminology

DOI: 10.3233/JAD-161148

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1153-1169, 2017

Authors: De Belder, Maya | Santens, Patrick | Sieben, Anne | Fias, Wim

Article Type: Research Article

Abstract: Background: Working memory (WM) problems are commonly observed in Alzheimer’s disease (AD), but the affected mechanisms leading to impaired WM are still insufficiently understood. The ability to efficiently process serial order in WM has been demonstrated to be fundamental to fluent daily life functioning. The decreased capability to mentally process serial position in WM has been put forward as the underlying explanation for generally compromised WM performance. Objective: Determine which mechanisms, such as order processing, are responsible for deficient WM functioning in AD. Method: A group of AD patients (n  = 32) and their partners (n  = 25), …assigned to the control group, were submitted to an extensive battery of neuropsychological and experimental tasks, assessing general cognitive state and functioning of several aspects related to serial order WM. Results: The results revealed an impaired ability to bind item information to serial position within WM in AD patients compared to controls. It was additionally observed that AD patients experienced specific difficulties with directing spatial attention when searching for item information stored in WM. Conclusion: The processing of serial order and the allocation of attentional resources are both disrupted, explaining the generally reduced WM functioning in AD patients. Further studies should now clarify whether this observation could explain disease-related problems for other cognitive functions such as verbal expression, auditory comprehension, or planning. Show more

Keywords: Alzheimer’s disease, attention, working memory

DOI: 10.3233/JAD-170193

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1171-1186, 2017

Authors: Hajipour, Mohammad Javad | Ghasemi, Forough | Aghaverdi, Haniyeh | Raoufi, Mohammad | Linne, Uwe | Atyabi, Fatemeh | Nabipour, Iraj | Azhdarzadeh, Morteza | Derakhshankhah, Hossein | Lotfabadi, Alireza | Bargahi, Afshar | Alekhamis, Zahra | Aghaie, Afsaneh | Hashemi, Ehsan | Tafakhori, Abbas | Aghamollaii, Vajiheh | Mashhadi, Marzie Maserat | Sheibani, Sara | Vali, Hojatollah | Mahmoudi, Morteza

Article Type: Research Article

Abstract: It is well understood that patients with different diseases may have a variety of specific proteins (e.g., type, amount, and configuration) in their plasmas. When nanoparticles (NPs) are exposed to these plasmas, the resulting coronas may incorporate some of the disease-specific proteins. Using gold (Au) NPs with different surface properties and corona composition, we have developed a technology for the discrimination and detection of two neurodegenerative diseases, Alzheimer’s disease (AD) and multiple sclerosis (MS). Applying a variety of techniques, including UV-visible spectra, colorimetric response analyses and liquid chromatography-tandem mass spectrometry, we found the corona-NP complexes, obtained from different human serums, …had distinct protein composition, including some specific proteins that are known as AD and MS biomarkers. The colorimetric responses, analyzed by chemometrics and statistical methods, demonstrate promising capabilities of the technology to unambiguously identify and discriminate AD and MS. The developed colorimetric technology might enable a simple, inexpensive and rapid detection/discrimination of neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, colorimetric technology, disease-specific protein corona, gold nanoparticles, multiple sclerosis

DOI: 10.3233/JAD-160206

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1187-1202, 2017

Authors: Lian, Yan | Xiao, Lily Dongxia | Zeng, Fan | Wu, Xianmu | Wang, Zhen | Ren, Hui

Article Type: Research Article

Abstract: Background: People can live well with dementia if they are diagnosed early and receive early interventions and appropriate dementia management and care. However, dementia is currently under-detected and under-diagnosed. The diagnosis rate is around 50% only in higher-income countries and 5–10% only in low- and middle-income countries. Studies on consumers’ experiences in engaging in dementia diagnosis in a socio-cultural context are much needed in order to generate research evidence to inform person-centered dementia care and services. Objective: The aim of the study was to understand the experiences of people with dementia and their caregivers in engaging in …dementia diagnosis. Methods: An interpretative study design informed by Gadamer’s hermeneutic principles was applied to the present study to achieve the aim of the study. The study was strengthened by applying a social ecological framework to the study design. In total, 23 participants contributed to the interviews or focus group. Thematic analysis was applied to data analysis. Results: Four themes were determined from data and described as: capabilities to detect the memory loss in an early stage, perceptions and beliefs of dementia in the community, different journeys toward the diagnosis and expectations of a smooth journey for others. These findings illuminate a social ecological perspective of improving early detection and timely diagnosis of dementia in the community settings. Conclusion: The findings of this study have implications for policy, resource, and practice development. Consumers expect that government subsidized dementia care services in primary care and specialist care settings are needed in order to enable consumer-driven timely diagnosis and dementia management in home care settings. Show more

Keywords: Alzheimer’s disease, dementia, timely diagnosis

DOI: 10.3233/JAD-170370

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1203-1211, 2017

Authors: De Lorenzi, Ersilia | Chiari, Marcella | Colombo, Raffaella | Cretich, Marina | Sola, Laura | Vanna, Renzo | Gagni, Paola | Bisceglia, Federica | Morasso, Carlo | Lin, Jennifer S. | Lee, Moonhee | McGeer, Patrick L. | Barron, Annelise E.

Article Type: Research Article

Abstract: Background: Identifying physiologically relevant binding partners of amyloid-β (Aβ) that modulate in vivo fibril formation may yield new insights into Alzheimer’s disease (AD) etiology. Human cathelicidin peptide, LL-37, is an innate immune effector and modulator, ubiquitous in human tissues and expressed in myriad cell types. Objective: We present in vitro experimental evidence and discuss findings supporting a novel hypothesis that LL-37 binds to Aβ42 and can modulate Aβ fibril formation. Methods: Specific interactions between LL-37 and Aβ (with Aβ in different aggregation states, assessed by capillary electrophoresis) were demonstrated by surface plasmon …resonance imaging (SPRi). Morphological and structural changes were investigated by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy. Neuroinflammatory and cytotoxic effects of LL-37 alone, Aβ42 alone, and LL-37/Aβ complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y). Results: SPRi shows binding specificity between LL-37 and Aβ, while TEM shows that LL-37 inhibits Aβ42 fibril formation, particularly Aβ’s ability to form long, straight fibrils characteristic of AD. CD reveals that LL-37 prevents Aβ42 from adopting its typical β-type secondary structure. Microglia-mediated toxicities of LL-37 and Aβ42 to neurons are greatly attenuated when the two peptides are co-incubated prior to addition. We discuss the complementary biophysical characteristics and AD-related biological activities of these two peptides. Conclusion: Based on this body of evidence, we propose that LL-37 and Aβ42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, cathelicidin, innate immunity, LL-37, microglia

DOI: 10.3233/JAD-170223

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1213-1226, 2017

Authors: Parsons, Thomas D. | Barnett, Michael

Article Type: Research Article

Abstract: Virtual reality-based neuropsychological assessments proffer the potential to address the limited ecological validity of pen-and-paper measures of memory. To investigate the construct validity of a newly developed virtual reality measure of memory, the Virtual Environment Grocery Store (VEGS), traditional neuropsychological measures of memory and executive functioning were administered to 48 older adults and 55 young adults. Performances on the VEGS memory tasks and the traditional neuropsychological assessments of memory were positively correlated, indicating that memory for VEGS content was similar to memory for traditional paper-and-pencil measures. The older adults performed significantly worse than young adults on the VEGS and the …California Verbal Learning Test, but the DKEFS Color-Word Interference failed to differentiate the groups. Furthermore, significant differences were found between groups for the VEGS memory and multitasking measures. The VEGS has the advantage over traditional measures of providing objective measurement of individual components of memory in simulations of everyday activities. Show more

Keywords: Aging, episodic memory, neuropsychological tests, prospective memory, validation studies, virtual reality

DOI: 10.3233/JAD-170295

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1227-1235, 2017

Authors: Kawalia, Shweta Bagewadi | Raschka, Tamara | Naz, Mufassra | de Matos Simoes, Ricardo | Senger, Philipp | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) progressively destroys cognitive abilities in the aging population with tremendous effects on memory. Despite recent progress in understanding the underlying mechanisms, high drug attrition rates have put a question mark behind our knowledge about its etiology. Re-evaluation of past studies could help us to elucidate molecular-level details of this disease. Several methods to infer such networks exist, but most of them do not elaborate on context specificity and completeness of the generated networks, missing out on lesser-known candidates. In this study, we present a novel strategy that corroborates common mechanistic patterns across large scale AD gene expression …studies and further prioritizes potential biomarker candidates. To infer gene regulatory networks (GRNs), we applied an optimized version of the BC3Net algorithm, named BC3Net10, capable of deriving robust and coherent patterns. In principle, this approach initially leverages the power of literature knowledge to extract AD specific genes for generating viable networks. Our findings suggest that AD GRNs show significant enrichment for key signaling mechanisms involved in neurotransmission. Among the prioritized genes, well-known AD genes were prominent in synaptic transmission, implicated in cognitive deficits. Moreover, less intensive studied AD candidates (STX2, HLA-F, HLA-C, RAB11FIP4, ARAP3, AP2A2, ATP2B4, ITPR2, and ATP2A3) are also involved in neurotransmission, providing new insights into the underlying mechanism. To our knowledge, this is the first study to generate knowledge-instructed GRNs that demonstrates an effective way of combining literature-based knowledge and data-driven analysis to identify lesser known candidates embedded in stable and robust functional patterns across disparate datasets. Show more

Keywords: Alzheimer’s disease, gene regulatory networks, microarray analysis, synaptic transmission

DOI: 10.3233/JAD-170011

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1237-1254, 2017

Authors: Wang, Dongmei | Liu, Xiaozhuan | Liu, Yumei | Li, Sanqiang | Wang, Chenying

Article Type: Research Article

Abstract: The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer’s disease (AD). Cardiotrophin-1 (CT-1) has been shown to exhibit impressive neuroprotective effects. Previous studies have shown positive effects of CT-1 on brain glucose metabolism and cognition in APPswe/PS1dE9 transgenic mice; however, little is known about the effects of CT-1 on early synaptic mitochondrial dysfunction and resultant synaptic pathology in the brain. In this study, 4-month-old transgenic mice with brain tissue-specific CT-1 expression were used alone or in combination with APPswe/PS1dE9 transgenic mice to evaluate the effect of CT-1 on synaptic mitochondrial dysfunction and resultant …synaptic pathology, and cryptic memory deficits in the APPswe/PS1dE9 transgenic mice. The potential mechanism of action of CT-1 was also examined. Young CT-1×APPswe/PS1dE9 transgenic mice exhibited improvements in long-term learning and memory ability and ameliorations of synaptic mitochondrial/synaptic impairments compared to young APPswe/PS1dE9 transgenic mice. Moreover, CT-1 upregulated the expression of AMPAR and increased AMP-activated protein kinase (AMPK) activity in the hippocampus of APPswe/PS1dE9 transgenic mice. However, AMPK inhibition through shRNA knockdown of AMPKα blocked the neuroprotective effects of CT-1 on the expression of AMPAR and mitochondrial/synaptic dysfunction in Aβ-treated mouse neurons. These results suggest that CT-1 may be a potent candidate for the early prevention and treatment of AD. Show more

Keywords: Alzheimer’s disease, AMPK, CT-1, mitochondrial pathology, synaptic dysfunction

DOI: 10.3233/JAD-170100

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1255-1267, 2017

Authors: Li, Chunfei | Loewenstein, David A. | Duara, Ranjan | Cabrerizo, Mercedes | Barker, Warren | Adjouadi, Malek | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Both amyloid (Aβ) load and APOE4 allele are associated with neurodegenerative changes in Alzheimer’s disease (AD) prone regions and with risk for cognitive impairment. Objective: To evaluate the unique and independent contribution of APOE4 allele status (E4+∖E4–), Aβ status (Amy+∖Amy–), and combined APOE4 and Aβ status on regional cortical thickness (CoTh) and cognition among participants diagnosed as cognitively normal (CN, n  = 251), early mild cognitive impairment (EMCI, n  = 207), late mild cognitive impairment (LMCI, n  = 196), and mild AD (n  = 162) from the ADNI. Methods: A series of two-way ANCOVAs with post-hoc Tukey HSD …tests, controlling independently for Aβ and APOE4 status and age were examined. Results: Among LMCI and AD participants, cortical thinning was widespread in association with Amy+ status, whereas in association with E4+ status only in the inferior temporal and medial orbito-frontal regions. Among CN and EMCI participants, E4+ status, but not Amy+ status, was independently associated with increased CoTh, especially in limbic regions [e.g., in the entorhinal cortex, CoTh was 0.123 mm greater (p  = 0.002) among E4+ than E4–participants]. Among CN and EMCI, both E4+ and Amy+ status were independently associated with cognitive impairment, which was greatest among those with combined E4 + and Amy+ status. Conclusion: Decreased CoTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4 + status is associated with increased CoTh, in medial and inferior temporal regions, although cognitive impairment at this state is independently associated with Amy+ and E4 + status. These findings imply a unique pathophysiological mechanism for E4 + status in AD and its progression. Show more

Keywords: ADNI, Alzheimer’s disease, amyloid, APOE, cortical thinning, memory, mild cognitive impairment

DOI: 10.3233/JAD-170286

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1269-1282, 2017