Journal of Alzheimer's Disease - Volume 61, issue 3

Authors: Power, Rebecca | Coen, Robert F. | Beatty, Stephen | Mulcahy, Riona | Moran, Rachel | Stack, Jim | Howard, Alan N. | Nolan, John M.

Article Type: Research Article

Abstract: Background: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso -zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties. Objective: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels. Methods: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n  = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z …(n  = 45) or placebo (n  = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured. Results: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p  = 0.009]; PAL errors [rANOVA, p  = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p  = 0.005) and observed increases in serum concentrations of L (p  = 0.009). Conclusion: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study. Show more

Keywords: Brain, CANTAB, carotenoids, cognitive function, episodic memory, lutein, meso-zeaxanthin, macular pigment, paired associated learning, zeaxanthin

DOI: 10.3233/JAD-170713

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 947-961, 2018

Authors: Chiziane, Elisabeth | Telemann, Henriette | Krueger, Martin | Adler, Juliane | Arnhold, Jürgen | Alia, A. | Flemmig, Jörg

Article Type: Research Article

Abstract: While the etiology of Alzheimer’s disease (AD) is still unknown, an increased formation of amyloid-β (Aβ) peptide and oxidative processes are major pathological mechanism of the disease. The interaction of Aβ with free heme leads to the formation of peroxidase-active Aβ-heme complexes. However, enzyme-kinetic data and systematic mutational studies are still missing. These aspects were addressed in this study to evaluate the role of Aβ-heme complexes in AD. The enzyme-kinetic measurements showed peroxidase-specific pH- and H2 O2 -dependencies. In addition, the enzymatic activity of Aβ-heme complexes constantly increased at higher peptide excess. Moreover, the role of the Aβ sequence for …the named enzymatic activity was tested, depicting human-specific R5, Y10, and H13 as essential amino acids. Also by studying Y10 as an endogenous peroxidase substrate for Aβ-heme complexes, ratio-specific effects were observed, showing an optimal dityrosine formation at an about 40-fold peptide excess. As dityrosine formation promotes Aβ fibrillation while free heme disturbs protein aggregation, we also investigated the effect of Aβ-heme complex-derived peroxidase activity on the formation of Aβ fibrils. The fluorescence measurements showed a different fibrillation behavior at strong peroxidase activity, leading also to altered fibril morphologies. The latter was detected by electron microscopy. As illustrated by selected in vivo measurements on a mouse model of AD, the disease is also characterized by Aβ-derived microvessel destructions and hemolytic processes. Thus, thrombo-hemorrhagic events are discussed as a source for free heme in brain tissue. In summary, we suggest the formation and enzymatic activity of Aβ-heme complexes as pathological key features of AD. Show more

Keywords: Alzheimer’s disease, Aβ-heme complexes, amyloid-β fibrillation, amyloid-β toxicity, free heme, hemolysis, peroxidase activity

DOI: 10.3233/JAD-170711

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 963-984, 2018

Authors: Papageorgiou, Sokratis G. | Voskou, Panagiota | Economou, Alexandra | Beratis, Ion | Douzenis, Athanasios

Article Type: Research Article

Abstract: Background: In current practice, it is common for the medical practitioner to assess a person’s testamentary capacity (TC) and give evidence to the Courts about a potential will contest. TC is an advanced cognitive activity that is both situation- and task-specific. Objective: The aim of the present study was the development of a brief, specialized instrument for TC assessment in patients with dementia. Method: We developed a short tool consisting of four subtests, assessing the person’s core functions which are required for TC: memory (orientation, autobiographical memory and realistic perception of beneficiaries), absence of serious psychopathology, …knowledge of financial parameters (value of assets, everyday life products, bills), and intention (vignettes, theory of mind). For its validation, we examined 64 outpatients from the Cognitive Disorders/Dementia Unit, 2nd Department of Behavioral Neurology, University of Athens. The decision of the expert served as the gold standard for the evaluation of TC. Results: Of the 64 participants, 39 were judged by the expert as capable of TC and the remaining 25 as incapable. For the total scale (maximum score of 48), the best combination of sensitivity (82.6%) and specificity (100%) was obtained for a cut-off score of 32/33. Cronbach’s alpha showed high levels of internal reliability for the scale (α = 0.86) and the point-biserial correlation coefficients showed high levels of criterion-related validity (rbp  = 0.797, p  < 0.001). Conclusion: The new instrument appears to be a reliable screening tool for the evaluation of TC in dementia, which can be used by both the expert and the non-expert. Further research is needed to confirm these promising findings. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, living wills, mental competency, neuropsychological tests, personal autonomy, volition, wills

DOI: 10.3233/JAD-170297

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 985-994, 2018

Authors: Wei, Eric X. | Oh, Esther S. | Harun, Aisha | Ehrenburg, Matthew | Agrawal, Yuri

Article Type: Research Article

Abstract: The vestibular system is an important contributor to balance control, spatial orientation, and falls risk. Recent evidence has shown that Alzheimer’s disease (AD) patients have a higher prevalence of vestibular impairment relative to healthy controls. We sought to evaluate whether vestibular loss is specifically associated with poor spatial cognitive skills among patients with mild cognitive impairment (MCI) and AD. We enrolled 50 patients (22 MCI and 28 AD) from an interdisciplinary Memory Clinic and measured vestibular physiologic function in all patients. Spatial cognitive function was assessed using the Money Road Map Test (MRMT) and the Trail Making Test Part B …(TMT-B). General cognitive function was assessed with the Mini-Mental Status Examination (MMSE). In multivariable linear regression analyses adjusted for age, gender, education level, and MMSE, MCI and AD patients with vestibular loss made significantly more errors on the MRMT relative to patients with normal vestibular function (β= 7.3, 95% CI 2.4, 12.1 for unilateral vestibular loss and β= 6.4, 95% CI 1.9, 10.9 for bilateral vestibular loss). We further stratified AD patients into “spatially normal” and “spatially impaired” groups based on MRMT performance, and found that the prevalence of vestibular loss was significantly higher in the spatially impaired AD group relative to the spatially normal AD group. These findings support the hypothesis that vestibular loss contributes specifically to a decline in spatial cognitive ability in MCI and AD patients, independently of general cognitive decline, and may predict a “spatially impaired” subtype of AD. Show more

Keywords: Alzheimer’s disease, Money Road Map Test, spatial cognition, vestibular system

DOI: 10.3233/JAD-170751

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 995-1003, 2018

Authors: Wang, Shan-Shan | Jia, Jianjun | Wang, Zhenfu

Article Type: Research Article

Abstract: Background: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been reported to exhibit therapeutic effects in various animal models of neurological diseases, such as stroke and hypoxic-ischemic brain injury. Objective: The present study investigated the potential beneficial effect of MSC-derived EVs in an animal model of Alzheimer’s disease (AD). Methods: APP/PS1 mice and their non-transgenic littermates (WT) received intracerebroventricle injection of MSC-derived EVs once per two days for two weeks. Then novel object recognition and water maze tasks were carried out to measure the cognitive behaviors. Electrophysiological tests were carried out to measure hippocampal synaptic plasticity. …Inducible nitric oxide synthase (iNOS) mRNA and protein levels were measured by qRT-PCR and western blotting in primary cultured neurons treated with amyloid-β peptide (Aβ) or prepared from APP/PS1 mice. Results: Treatment with MSC-derived EVs alleviates exogenous Aβ-induced iNOS mRNA and protein expression. In cultured primary neurons prepared from APP/PS1 pups, iNOS mRNA and protein levels were significantly reduced when treated with MSC-derived EVs. MSC-derived EVs improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation in APP/PS1 mice. Conclusion: MSC-derived EVs possessed beneficial effects in a mouse model of AD, probably by suppressing Aβ induced iNOS expression. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, extracellular vesicles, iNOS, mesenchymal stem cells

DOI: 10.3233/JAD-170848

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1005-1013, 2018

Authors: Fan, Yu | Luo, Rongcan | Su, Ling-Yan | Xiang, Qun | Yu, Dandan | Xu, Ling | Chen, Jia-Qi | Bi, Rui | Wu, Dong-Dong | Zheng, Ping | Yao, Yong-Gang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease with increasing incidence across the world and no cure at the present time. An ideal animal model would facilitate the understanding of the pathogenesis of AD and discovery of potential therapeutic targets. The Chinese tree shrew (Tupaia belangeri chinensis ) has a closer genetic affinity to primates relative to rodents, and can attain ages of 8 years or older, which represents another advantage for the study of neurodegenerative diseases such as AD compared to primates. Here, we analyzed 131 AD-related genes in the Chinese tree shrew brain tissues based on protein sequence identity, …positive selection, mRNA, and protein expression by comparing with those of human, rhesus monkey, and mouse. In particular, we focused on the Aβ and neurofibrillary tangles formation pathways, which are crucial to AD pathogenesis. The Chinese tree shrew had a generally higher sequence identity with human than that of mouse versus human for the AD pathway genes. There was no apparent selection on the tree shrew lineage for the AD-related genes. Moreover, expression pattern of the Aβ and neurofibrillary tangle formation pathway genes in tree shrew brain tissues resembled that of human brain tissues, with a similar aging-dependent effect. Our results provided an essential genetic basis for future AD research using the tree shrew as a viable model. Show more

Keywords: AD pathway, Alzheimer’s disease, animal model, Chinese tree shrews, mRNA expression profiling

DOI: 10.3233/JAD-170594

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1015-1028, 2018

Authors: Takenoshita, Shintaro | Terada, Seishi | Yokota, Osamu | Kutoku, Yumiko | Wakutani, Yosuke | Nakashima, Makoto | Maki, Yohko | Hattori, Hideyuki | Yamada, Norihito

Article Type: Research Article

Abstract: Social cognition has recently been recognized as one of the essential cognitive domains. Some reports suggested that patients with Alzheimer’s disease dementia (ADD) presented significant theory of mind deficits even in the mild condition. However, most previous studies included only small numbers of patients with ADD. The present study administered the first-order false belief (Sally-Anne) test to 116 consecutive patients with ADD from the outpatient units of the Memory Clinic and compared the characteristics of the two groups with correct and incorrect answers on the test. Then various clinical characteristics were evaluated. Only 37.1% of patients with ADD correctly answered …the Sally-Anne test with the right explanation. Comparison between the two groups of correct and incorrect answers revealed a significant association between the frontal assessment battery score and the result of the Sally-Anne test in the multiple logistic regression analyses. Thus, patients with ADD presented a significant deficit in social cognition even in the mild condition. Frontal dysfunction was thought to be related to the deficits in mild ADD. Show more

Keywords: Alzheimer’s disease, case control studies, cognition, dementia, neuropsychological test, prospective studies, theory of mind

DOI: 10.3233/JAD-170621

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1029-1036, 2018

Authors: Ishikawa, Ai | Tokunaga, Masaki | Maeda, Jun | Minamihisamatsu, Takeharu | Shimojo, Masafumi | Takuwa, Hiroyuki | Ono, Maiko | Ni, Ruiqing | Hirano, Shigeki | Kuwabara, Satoshi | Ji, Bin | Zhang, Ming-Rong | Aoki, Ichio | Suhara, Tetsuya | Higuchi, Makoto | Sahara, Naruhiko

Article Type: Research Article

Abstract: Background: Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood. Objective: We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model. Methods: rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [11 C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [11 C]AC-5216 were used to visualize …tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry. Results: PET studies revealed age-dependent increases in [11 C]PBB3 and [11 C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [11 C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [11 C]AC-5216 disappeared after age 7 months. In contrast, [11 C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia. Conclusion: Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [11 C]PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains. Show more

Keywords: Neuroinflammation, tau-PET, tauopathy, transgenic mice, TSPO, volumetric MRI

DOI: 10.3233/JAD-170509

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1037-1052, 2018

Authors: Zanardini, Roberta | Benussi, Luisa | Fostinelli, Silvia | Saraceno, Claudia | Ciani, Miriam | Borroni, Barbara | Padovani, Alessandro | Binetti, Giuliano | Ghidoni, Roberta

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes …than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN -mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies. Show more

Keywords: Adipokines, C-peptide, FTLD, ghrelin, haploinsufficiency, resistin, serum, visfatin

DOI: 10.3233/JAD-170747

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1053-1060, 2018

Authors: Volpina, Olga M. | Samokhin, Alexandr N. | Koroev, Dmitriy O. | Nesterova, Inna V. | Volkova, Tatyana D. | Medvinskaya, Natalia I. | Nekrasov, Pavel V. | Tatarnikova, Olga G. | Kamynina, Anna V. | Balasanyants, Samson M. | Voronina, Tamara A. | Kulikov, Alexey M. | Bobkova, Natalia V.

Article Type: Research Article

Abstract: Activation of receptor for advanced glycation end products (RAGE) plays an essential role in the development of Alzheimer’s disease (AD). It is known that the soluble isoform of the receptor binds to ligands and prevents negative effects of the receptor activation. We proposed that peptide fragments from RAGE prevent negative effects of the receptor activation during AD neurodegeneration. We have synthesized peptide fragments from surface-exposed regions of RAGE. Peptides were intranasally administrated into olfactory bulbectomized (OBX) mice, which developed some characteristics similar to AD neurodegeneration. We have found that only insertion of fragment (60–76) prevents the memory of OBX mice. …Immunization of OBX mice with peptides showed that again only (60–76) peptide protected the memory of animals. Both intranasal insertion and immunization decreased the amyloid-β (Aβ) level in the brain. Activity of shortened fragments of (60–76) peptide was tested and showed only the (60–70) peptide is responsible for manifestation of activity. Intranasal administration of (60–76) peptide shows most protective effect on morpho-functional characteristics of neurons in the cortex and hippocampal areas. Using Flu-(60–76) peptide, we revealed its penetration in the brain of OBX mice as well as colocalization of Flu-labeled peptide with Aβ in the brain regions in transgenic mice. Flu-(60–76) peptide complex with trimer of Aβ was detected by SDS-PAGE. These data indicate that Aβ can be one of the molecular target of (60–70) peptide. These findings provide a new peptide molecule for design of anti-AD drug and for investigation of RAGE activation ways in progression of AD neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid-β , peptides, receptor for advanced glycation end products

DOI: 10.3233/JAD-170483

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1061-1076, 2018