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

Authors: Baird, Amee | Thompson, William Forde

Article Type: Review Article

Abstract: In this review, we consider how the onset and progression of dementia can disrupt one’s sense of self, and propose that music is an ideal tool for alleviating this distressing symptom. Various aspects of the self can be impaired in people with dementia, depending on how the self is defined. There are anecdotal reports that music can ‘bring people back to themselves’ in the face of dementia, but there have been scarce empirical investigations of this topic. Motivated by a consideration of the existing literature, we outline a novel theoretical framework that accounts for the relationship between music and the …self in people with dementia. We propose that music has a number of ‘design features’ that make it uniquely equipped to engage multiple aspects of the self. We suggest that each design feature interacts with different aspects of the self to varying degrees, promoting overall wellbeing. We discuss how existing research on music and dementia fits within this framework, and describe two case studies in which music was an ideal stimulus for reaffirming their sense of self. Our framework may be useful for the diagnosis and treatment of impairments of self in people with dementia, and highlights how music, given its ability to engage all aspects of the self simultaneously, can result in an overall enhanced sense of self. Show more

Keywords: Alzheimer’s disease, dementia, music, self

DOI: 10.3233/JAD-170737

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 827-841, 2018

Authors: Reddy, P. Hemachandra | Manczak, Maria | Yin, Xiangling | Grady, Mary Catherine | Mitchell, Andrew | Tonk, Sahil | Kuruva, Chandra Sekhar | Bhatti, Jasvinder Singh | Kandimalla, Ramesh | Vijayan, Murali | Kumar, Subodh | Wang, Rui | Pradeepkiran, Jangampalli Adi | Ogunmokun, Gilbert | Thamarai, Kavya | Quesada, Kandi | Boles, Annette | Reddy, Arubala P.

Article Type: Review Article

Abstract: The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer’s disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of …AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin’s bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, curcumin, mitochondria, oxidative stress, reactive oxygen species

DOI: 10.3233/JAD-170512

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 843-866, 2018

Authors: Botchway, Benson O.A. | Moore, Masania K. | Akinleye, Faith O. | Iyer, Ishwari C. | Fang, Marong

Article Type: Review Article

Abstract: Since its discovery some hundred years ago, Alzheimer’s disease (AD), a neurodegenerative disease and an eminent cause of most dementia, continues to pose problems for affected families and society, especially in developed countries. With the approved medications by the Food and Drugs Administration in the United States, effectual treatment of AD apropos to the complete eradication of the disease continues to be elusive due to complexities relating to the pathophysiology of the disease. Nutrition has and continues to play a salient role in the survival of living organisms with no exception for human beings. Herein, we report the connection between …nutrition and AD with particular attention to vitamins, curcumin, and the Mediterranean diet. Show more

Keywords: Alzheimer’s disease, curcumin, dementia, Mediterranean diet, neurodegenerative, nutrition, vitamins

DOI: 10.3233/JAD-170874

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 867-883, 2018

Authors: Jonveaux, Thérèse Rivasseau | Fescharek, Reinhard

Article Type: Research Article

Abstract: The creation of healing gardens for persons with Alzheimer’s disease and related diseases (ADRD) offers vast potential. They can play a role in the scaffolding of cognitive disorders, emotional stress, sensory processing, sense of harmony, and appeasement. These effects are achieved through a distributed interplay of psychological functions with the immediate environment and local culture on the one hand, and dialogue on the other. The garden, a natural canvas created by man, shares with art the ability to foster an esthetic sense for which the perception can be measured by functional neurological imaging exploration. Art represents a mediator for the …collaborative realization of distributed psychological functions between different individuals. Based on the hypothesis of an optimization of the therapeutic potential of a garden by a design adapted to the neuro-psycho-social and cultural specificities of its users combined with the thoughtful introduction of an artistic dimension, the “art, memory and life ” healing garden was created at the University Hospital of Nancy as a prototype for persons with ADRD. The design concept was based on two hypotheses that we formulate herein, discuss their theoretical foundation, and suggest enhanced design for therapeutic gardens based upon our experience. Show more

Keywords: Alzheimer’s disease, art, beauty, cognition, healing gardens, interaction

DOI: 10.3233/JAD-170781

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 885-898, 2018

Authors: Brici, David | Götz, Jürgen | Nisbet, Rebecca M.

Article Type: Short Communication

Abstract: Alzheimer’s disease is characterized by two main pathological hallmarks in the human brain: the extracellular deposition of amyloid-β as plaques and the intracellular accumulation of the hyperphosphorylated protein tau as neurofibrillary tangles (NFTs). Phosphorylated tau (p-tau) specific-antibodies and silver staining have been used to reveal three morphological stages of NFT formation: pre-NFTs, intraneuronal NFTs (iNFTs), and extraneuronal NFTs (eNFTs). Here we characterize a novel monoclonal antibody, RN235, which is specific for tau phosphorylated at serine 235, and detects iNFTs and eNFTs in brain tissue, suggesting that phosphorylation at this site is indicative of late stage changes in tau.

Keywords: Alzheimer’s disease, antibody, frontotemporal lobar degeneration, neurofibrillary tangle, tau

DOI: 10.3233/JAD-170610

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 899-905, 2018

Authors: Rozzini, Luca | Lanfranchi, Francesco | Pilotto, Andrea | Catalani, Simona | Gilberti, Maria Enrica | Paganelli, Matteo | Apostoli, Pietro | Padovani, Alessandro

Article Type: Short Communication

Abstract: Several studies showed high serum copper levels in Alzheimer’s disease (AD). The present study applied a newly developed method to detect serum copper free from proteins (free-Cu). Forty-four patients affected by dementia due to AD, thirty-six patients affected by mild cognitive impairment (MCI) due to AD, and twenty-eight healthy controls underwent clinical, cognitive, and MRI assessment. The new method showed higher free-Cu concentrations in MCI and dementia due to AD compared to controls (p  < 0.0001). No correlation between copper levels, cognitive or MRI measures were found.

Keywords: Alzheimer’s disease, amyloid beta-protein, copper, dementia, medial temporal lobe atrophy, mild cognitive impairment

DOI: 10.3233/JAD-170552

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 907-912, 2018

Authors: Shea, Thomas B. | Remington, Ruth

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) can be preceded by subtle memory decline that can last a decade or more before progressing to what would be diagnosed as the mild cognitive impairment stage. During this early stage of decline, individuals and even their caregivers can fail to perceive any serious difficulty or need to consult a physician. Herein, we present evidence in support of these concerns, and demonstrate how this can interfere not only with clinical trials of AD but also those involving cognitive performance of elderly individuals without intentional reference to AD.

Keywords: Cognitive decline, executive function, Mini-Mental State Exam, outliers, self-report, Trail-making test

DOI: 10.3233/JAD-170794

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 913-915, 2018

Authors: Emrani, Sheina | Libon, David J. | Lamar, Melissa | Price, Catherine C. | Jefferson, Angela L. | Gifford, Katherine A. | Hohman, Timothy J. | Nation, Daniel A. | Delano-Wood, Lisa | Jak, Amy | Bangen, Katherine J. | Bondi, Mark W. | Brickman, Adam M. | Manly, Jennifer | Swenson, Rodney | Au, Rhoda | on behalf of the Consortium for Clinical and Epidemiological Neuropsychological Data Analysis (CENDA)

Article Type: Research Article

Abstract: Background: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined. Objective: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI). Methods: Memory clinic patients (n  = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking …participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied. Results: A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p  < 0.003) serial position 4 (p  < 0.002); and lower than both group for serial position 5 (recency; p  < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p  < 0.010); and more omissions (p  < 0.020), and perseverations errors (p  < 0.018) than non-MCI patients. Conclusions: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI. Show more

Keywords: Boston process approach, digit span, executive functions, mild cognitive impairment, serial order, working memory

DOI: 10.3233/JAD-170555

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 917-928, 2018

Authors: Atanasova, Boriana | Mondon, Karl | Dreyfuss, Lise | Beaufils, Emilie | Desmidt, Thomas | Hommet, Caroline | El-Hage, Wissam | Belzung, Catherine

Article Type: Research Article

Abstract: Background: Several clinical studies concerning the olfactory function of patients with cognitive impairment have used sensory scales to investigate hedonic perception. However, no study has focused on the choice of the most appropriate sensory hedonic scale for the individuals with neurodegenerative disorders or other psychiatric diseases involving cognitive deficits. Objective: The aim of this study was to investigate the ability of patients with Alzheimer’s disease (AD) to use two hedonic scales (category scale and linear scale) and compare their discriminatory capacity, repeatability, and ease of use. This should allow us to identify the most appropriate hedonic scale for …patients with AD. Methods: We recruited 18 patients with mild to moderate AD, and 20 healthy volunteers matched for gender, age, smoking status, and educational level. The participants underwent a clinical assessment and hedonic evaluation of three odorants (pleasant, unpleasant, and neutral), using a five-point category scale and a 10-cm linear scale with a marked mid-point. Results: AD patients were able to use hedonic scales as well as paired healthy elderly subjects. The linear scale performed slightly better in terms of ease of use for both patients and healthy controls and discriminatory capacity for AD patients. The results for AD patients and controls with both scales were repeatable. Conclusion: The linear scale may be more appropriate for AD patients pending further studies involving a larger population of patients, using several odorants. Show more

Keywords: Alzheimer’s disease, five-point category scale, hedonic evaluation, linear scale, olfaction

DOI: 10.3233/JAD-170433

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 929-938, 2018

Authors: Lövheim, Hugo | Olsson, Jan | Weidung, Bodil | Johansson, Anders | Eriksson, Sture | Hallmans, Göran | Elgh, Fredrik

Article Type: Research Article

Abstract: Background: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer’s disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies. Objective: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD. Methods: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), …and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses. Results: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p  = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p  < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p  = 0.007). Conclusion: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system. Show more

Keywords: Alzheimer’s disease, cytomegalovirus, dementia, Herpes simplex virus, nested case-control study

DOI: 10.3233/JAD-161305

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 939-945, 2018

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

Authors: Liu, Guiyou | Zhang, Yan | Wang, Longcai | Xu, Jianyong | Chen, Xiaoyun | Bao, Yunjuan | Hu, Yang | Jin, Shuilin | Tian, Rui | Bai, Weiyang | Zhou, Wenyang | Wang, Tao | Han, Zhifa | Zong, Jian | Jiang, Qinghua

Article Type: Research Article

Abstract: Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimer’s disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale …eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk. Show more

Keywords: Alzheimer’s disease, EPHA1, eQTLs, genome-wide association study

DOI: 10.3233/JAD-170468

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1077-1088, 2018

Authors: Siddarth, Prabha | Rahi, Berna | Emerson, Natacha D. | Burggren, Alison C. | Miller, Karen J. | Bookheimer, Susan | Lavretsky, Helen | Dobkin, Bruce | Small, Gary | Merrill, David A.

Article Type: Research Article

Abstract: Background: Physical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited. Objective: To examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints. Methods: Twenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day …determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups. Results: Twenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n  = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p  = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p  = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p  = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p  = 0.05). Memory recall was not significantly different between the two groups. Conclusion: Older non-demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy. Show more

Keywords: Cortical thickness, memory complaints, older adults, physical activity

DOI: 10.3233/JAD-170586

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1089-1096, 2018

Authors: Gabriel, António José | Almeida, Maria Rosário | Ribeiro, Maria Helena | Carneiro, Diogo | Valério, Daniela | Pinheiro, Ana Cristina | Pascoal, Rui | Santana, Isabel | Baldeiras, Inês

Article Type: Research Article

Abstract: Background: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited. Objective: To investigate the influence of the BuChE-K variant in MCI progression to AD. Methods: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels …of AD biomarkers amyloid-β 42 (Aβ42 ), total and hyperphosphorylated tau (t-tau and p-tau) were also determined. Results: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ 4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ 4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD. Conclusion: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ 4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients. Show more

Keywords: Alzheimer’s disease, butyrylcholinesterase, disease progression, mildcognitive impairment

DOI: 10.3233/JAD-170695

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1097-1105, 2018

Authors: Renard, Dimitri | Collombier, Laurent | Demattei, Christophe | Wacongne, Anne | Charif, Mahmoud | Ayrignac, Xavier | Azakri, Souhayla | Gaillard, Nicolas | Boudousq, Vincent | Lehmann, Sylvain | Menjot de Champfleur, Nicolas | Thouvenot, Eric

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-β (Aβ) imaging (using 11 C-Pittsburgh compound B and 18 F-florbetapir, but not 18 F-florbetaben). Objective: To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18 F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients. Methods: CSF levels of total tau, phosphorylated tau, Aβ1-42 , and Aβ1-40 , MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET …(using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients. Results: A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aβ1-40 levels (rho = –0.83, p  = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p  = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = –0.63, p  = 0.076; phosphorylated tau, rho = –0.68, p  = 0.05; Aβ1-42 , rho = –0.59, p  = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = –0.50, p  = 0.18) was observed between CSF Aβ1-40 levels and cerebral microbleed numbers. Conclusion: In CAA-ri, CSF Aβ1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aβ1-40 as an in vivo marker for CAA and CAA-ri. Show more

Keywords: Amyloid, florbetaben, imaging

DOI: 10.3233/JAD-170843

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1107-1117, 2018

Authors: Subic, Ana | Cermakova, Pavla | Religa, Dorota | Han, Shuang | von Euler, Mia | Kåreholt, Ingemar | Johnell, Kristina | Fastbom, Johan | Bognandi, Liselia | Winblad, Bengt | Kramberger, Milica G. | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF). Objective: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF. Methods: Of 49,792 patients registered in the Swedish Dementia Registry 2007–2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death. Results: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 …(37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p  < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59–0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01–1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03–1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment. Conclusions: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible. Show more

Keywords: Atrial fibrillation, dementia, hemorrhage, ischemic stroke, warfarin

DOI: 10.3233/JAD-170575

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1119-1128, 2018

Authors: Pastori, Daniele | Miyazawa, Kazuo | Lip, Gregory Y.H.

Article Type: Article Commentary

Abstract: The risk of developing dementia is increased in patients with atrial fibrillation (AF), with the incidence of both conditions increasing with aging. Patients with dementia frequently do not receiving adequate thrombo-prophylaxis, because of the inability to monitor INR and/or to achieve and maintain good compliance with anticoagulant treatment. Under-treatment is therefore an important contributor to the increased risk of ischemic stroke and mortality in this subgroup of AF patients. In newly-diagnosed patients with AF starting oral anticoagulation, the presence of cognitive impairment should be considered in addition to the calculation of the SAMe-TT2 R2 score, as part of an …integrated decision management pathway to choose the most appropriate oral anticoagulant [i.e., vitamin K antagonists (VKAs) or non-vitamin K oral anticoagulants (NOACs)]. Moreover, in patients with low or worsening time in therapeutic range during VKAs therapy, the assessment of cognitive impairment may help identify those patients who may benefit from switching to NOACs. In conclusion, patients with AF and dementia benefit from anticoagulation and should not be denied receiving adequate stroke prevention. Cognitive function assessment and social support are pivotal elements in the management of these AF patients. Show more

Keywords: Anticoagulation, atrial fibrillation, dementia, ischemic stroke, mortality

DOI: 10.3233/JAD-170955

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1129-1132, 2018

Authors: Heinrich, Juliette | Vidal, Jean-Sébastien | Simon, Axelle | Rigaud, Anne-Sophie | Hanon, Olivier | Epelbaum, Jacques | Viollet, Cecile | Duron, Emmanuelle

Article Type: Research Article

Abstract: Background: Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML. Objective: To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI. Methods: Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. …Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens’ scale and WML according to Fazekas criteria. Results: Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p  = 0.007), lower BMI (p  = 0.08), lower MMSE score (p  = 0.05), lower FCRST (p  = 0.008), hippocampal atrophy (p  = 0.04), periventricular WML (p  = 0.007), and deep WML burden (p  = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4–35.13), p  = 0.02) remained associated with low BSIT score independently from hippocampal atrophy. Conclusion: In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing. Show more

Keywords: Brain white matter lesions, magnetic resonance imaging, mild cognitive impairment, olfaction

DOI: 10.3233/JAD-170378

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1133-1141, 2018

Authors: Raha-Chowdhury, Ruma | Henderson, James W. | Raha, Animesh Alexander | Stott, Simon R.W. | Vuono, Romina | Foscarin, Simona | Wilson, Liam | Annus, Tiina | Fincham, Robert | Allinson, Kieren | Devalia, Vinod | Friedland, Robert P. | Holland, Anthony | Zaman, Shahid H.

Article Type: Research Article

Abstract: Background: Down syndrome (DS; trisomy 21) individuals have a spectrum of hematopoietic and neuronal dysfunctions and by the time they reach the age of 40 years, almost all develop Alzheimer’s disease (AD) neuropathology which includes senile plaques and neurofibrillary tangles. Inflammation and innate immunity are key players in AD and DS. Triggering receptor expressed in myeloid cells-2 (TREM2) variants have been identified as risk factors for AD and other neurodegenerative diseases. Objective: To investigate the effects of TREM2 and the AD-associated R47H mutation on brain pathology and hematopoietic state in AD and DS. Methods: We analyzed …peripheral blood, bone marrow, and brain tissue from DS, AD, and age-matched control subjects by immunohistochemistry and western blotting. TREM2-related phagocytosis was investigated using a human myeloid cell line. Results: TREM2 protein levels in brain and sera declined with age and disease progression in DS. We observed soluble TREM2 in brain parenchyma that may be carried by a subset of microglia, macrophages, or exosomes. Two DS cases had the AD-associated TREM2-R47H mutation, which manifested a morphologically extreme phenotype of megakaryocytes and erythrocytes in addition to impaired trafficking of TREM2 to the erythroid membrane. TREM2 was shown to be involved in phagocytosis of red blood cells. TREM2 was seen in early and late endosomes. Silencing TREM2 using siRNA in THP1 cells resulted in significant cell death. Conclusion: We provide evidence that peripheral TREM2 originating from erythromyeloid cells significantly determines AD neuropathology in DS subjects. Understanding the molecular signaling pathways mediated by TREM2 may reveal novel therapeutic targets. Show more

Keywords: Alzheimer’s disease, dementia, Down syndrome, innate immunity, immunomodulation, inflammation, myelination, myeloid hypothesis, neurodegeneration, soluble TREM2

DOI: 10.3233/JAD-170814

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1143-1162, 2018

Authors: Sundermann, Erin E. | Edmonds, Emily C. | Delano-Wood, Lisa | Galasko, Douglas R. | Salmon, David P. | Rubin, Leah H. | Bondi, Mark W. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer’s disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer’s Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into “overestimates,” “comparable estimates”, and “underestimates” of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC …and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of “overestimates” in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to “comparable estimates,” “underestimates” of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC. Show more

Keywords: Alzheimer’s disease, amyloid, awareness, cognitive reserve, mild cognitive impairment, sex differences memory

DOI: 10.3233/JAD-170425

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1163-1178, 2018

Authors: Maletta, Raffaele | Smirne, Nicoletta | Bernardi, Livia | Anfossi, Maria | Gallo, Maura | Conidi, Maria Elena | Colao, Rosanna | Puccio, Gianfranco | Curcio, Sabrina A.M. | Laganà, Valentina | Frangipane, Francesca | Cupidi, Chiara | Mirabelli, Maria | Vasso, Franca | Torchia, Giusi | Muraca, Maria G. | Di Lorenzo, Raffaele | Rose, Giuseppina | Montesanto, Alberto | Passarino, Giuseppe | Bruni, Amalia C.

Article Type: Research Article

Abstract: Background: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer’s disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed. Objectives: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia. Methods: The …genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin. Results: Carriers of at least one APOE ɛ 4 allele resulted to be at higher risk of AD [OR(95% CI) = 2.721(1.477–5.011)] and VaD [OR(95% CI) = 6.205(2.356–16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI) = 2.427(1.364–4.319)] and VaD [OR(95% CI) = 3.649(1.455–9.152)] compared to subjects with the II-VV genotypes. Conclusion: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOE ɛ 4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia. Show more

Keywords: Alzheimer’s disease, APOE, cerebrovascular, CETP I405V, dementia, genetic, risk factors, vascular dementia

DOI: 10.3233/JAD-170687

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1179-1187, 2018

Authors: Nielsen, Malene Schjnning | Simonsen, Anja Hviid | Siersma, Volkert | Hasselbalch, Steen Gregers | Hoegh, Peter

Article Type: Research Article

Abstract: Background: Daily living requires the ability to perform dual-tasking. As cognitive skills decrease in dementia, performing a cognitive and motor task simultaneously become increasingly challenging and subtle gait abnormalities may even be present in pre-dementia stages. Therefore, a dual-tasking paradigm, such as the Timed Up and Go-Dual Task (TUG-DT), may be useful in the diagnostic assessment of mild cognitive impairment (MCI). Objective: To investigate the diagnostic and prognostic ability of a dual-tasking paradigm in patients with MCI or mild Alzheimer’s disease (AD) and to evaluate the association between the dual-tasking paradigm and cerebrospinal fluid (CSF) AD biomarkers. …Methods: The study is a prospective cohort study conducted in a clinical setting in two memory clinics. Eighty-six patients were included (28 MCI, 17 AD, 41 healthy controls (HC)). The ability to perform dual-tasking was evaluated by the TUG-DT. Patients underwent a standardized diagnostic assessment and were evaluated to determine progression yearly. Results: ROC curve analysis illustrated a high discriminative ability of the dual-tasking paradigm in separating MCI patients from HC (AUC: 0.78, AUC: 0.82) and a moderate discriminative ability in separating MCI from AD (AUC: 0.73, AUC: 0.55). Performance discriminated clearly between all groups (p  < 0.01). Logistic regression analyses revealed a low prognostic value of the dual-tasking paradigm for progression and rate of cognitive decline. A moderately strong correlation between the dual-tasking paradigm and CSF AD biomarkers was observed. Conclusion: In our study, we found that patients with MCI and mild AD have increasing difficulties in dual-tasking compared to healthy elderly. Hence, the dual-tasking paradigm may be a potential complement in the diagnostic assessment in a typical clinical setting. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, diagnosis, gait, mild cognitive impairment, motor control, prognosis

DOI: 10.3233/JAD-161310

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1189-1199, 2018

Authors: Arner, Andrew | Rockenstein, Edward | Mante, Michael | Florio, Jazmin | Masliah, Deborah | Salehi, Bahar | Adame, Anthony | Overk, Cassia | Masliah, Eliezer | Rissman, Robert A.

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD …neuropathology. Mice were analyzed at 3 and 6 months of age for pathological and behavioral endpoints. While both the 3RTau and the hAPP-3RTau mice showed neuronal loss, increased tau aggregation, Aβ plaques and exhibited more behavioral deficits compared to the non-tg control, the bigenic mice often displaying relatively worsening levels. We found that even in young animals we found that the presence of APP/Aβ increased the accumulation of 3R tau in the neocortex and hippocampus. This observation was accompanied by activation of GSK3 and neurodegeneration in the neocortex and CA1 region. These results suggest that in addition to 4R tau, APP/Aβ may also enhance accumulation of 3R tau, a process which may be directly relevant to pathogenic pathways in AD. Our results demonstrate that this bigenic model closely parallels the pathological course of AD and may serve as a valuable model for testing new pharmacological interventions. Show more

Keywords: 3R tau, Alzheimer’s disease, amyloid-β, hippocampus, mouse, Pick’s disease, tau phosphorylation, transgenic

DOI: 10.3233/JAD-170388

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1201-1219, 2018

Authors: Eldholm, Rannveig Sakshaug | Barca, Maria Lage | Persson, Karin | Knapskog, Anne-Brita | Kersten, Hege | Engedal, Knut | Selbæk, Geir | Brækhus, Anne | Skovlund, Eva | Saltvedt, Ingvild

Article Type: Research Article

Abstract: Background: The course of Alzheimer’s disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression. Objective: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0–18), the cognitive test Mini-Mental State Examination (MMSE, 0–30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1). Methods: The Progression of AD …and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics. Results: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16–37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores. Conclusion: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia, mild cognitive impairment, prognosis, progression

DOI: 10.3233/JAD-170436

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1221-1232, 2018

Authors: Nikolai, Tomas | Stepankova, Hana | Kopecek, Miloslav | Sulc, Zdenek | Vyhnalek, Martin | Bezdicek, Ondrej

Article Type: Research Article

Abstract: Background: Outside of the United States, international perspectives on normative data for neuropsychological test performance, within diverse populations, have been scarce. The neuropsychological test battery from the Uniform Data Set (UDS) of the Alzheimer’s Disease Centers (ADC) program of the United States National Institute on Aging (NIA) is one of the most sensitive batteries for the evaluation of both normal cognitive aging and pathological cognitive decline. Objective: This study aimed to determine the feasibility of the Czech Neuropsychological Test Battery from the Uniform Data Set (UDS-Cz 2.0), while also evaluating the results obtained from an international perspective. …Methods: This paper describes data from 520 cognitively normal participants. Regression analyses were used to describe the influence of demographic variables on UDS-Cz test performance. Results: Cognitive performance on all measures declined with age, with patient education level serving as a protective factor. Therefore, the present study provides normative data for the UDS-Cz, adjusted for the demographic variables of age and education. Conclusion: The present study determines the psychometric properties of the UDS-Cz and establishes normative values in the aging Czech population, which can be used in clinical settings. Show more

Keywords: Aging, Alzheimer’s disease, healthy subjects, normative

DOI: 10.3233/JAD-170595

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1233-1240, 2018

Authors: Snir, Jonatan A. | Suchy, Mojmir | Bindseil, Geron A. | Kovacs, Michael | Chronik, Blaine A. | Hudson, Robert H.E. | Pasternak, Stephen H. | Bartha, Robert

Article Type: Research Article

Abstract: Background: Early detection of Alzheimer’s disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes. Objective: To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68 Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates. Methods: The targeted CA consisted of an HIV-1 Tat cell …penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68 Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n  = 5–8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18 F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake. Results: The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls. Conclusions: Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent. Show more

Keywords: Alzheimer’s disease, cathepsin D, mice, molecular imaging, radionuclide imaging

DOI: 10.3233/JAD-170115

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1241-1252, 2018