Journal of Alzheimer's Disease - Volume 66, issue 3

Authors: Cabinio, Monia | Saresella, Marina | Piancone, Federica | LaRosa, Francesca | Marventano, Ivana | Guerini, Franca Rosa | Nemni, Raffaello | Baglio, Francesca | Clerici, Mario

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative condition characterized by memory impairment and general decrease in cognitive functions and daily living competences, that leads to a complete loss of autonomy. The pathogenesis of AD is characterized by the deposition of amyloid-β plaques (Aβ plaques) and neurofibrillary tangles, initially involving cortical and hippocampal structures, and neuroinflammation. To date, no studies have investigated the topological association between neuroinflammation and hippocampal shape in AD. Objective: The aim of the present study is to assess the association between hippocampal shape, cognitive profile, and neuroinflammation in a group of AD patients in the …mild stage of the disease. Methods: Thirty-one patients with typical onset AD (mild stage) underwent MRI examination (1.5T scanner); hippocampal structures were segmented using a vertex-wise analysis (FSL-FIRST). Immune parameters were evaluated on peripheral blood mononuclear cells by flow-cytometry. Correlation analyses were performed between hippocampal shape and both cognitive profile (ADAS-Cog and MMSE scores), and neuro-inflammatory variables (i.e., circulating monocytes, cytokines). Results: Statistically significant correlations (p  < 0.05FWE ) between right hippocampal shape and cognitive measurements and between left hippocampal shape and inflammatory indices were detected. The hippocampal field mostly involved was the lateral portion of bilateral hippocampi, mainly overlapping with Cornu Ammonis, extending along the entire longitudinal axis. Conclusions: A topological relationship between hippocampal atrophy and both cognitive profile and neuroinflammation is found; the association with neuroinflammatory indices is in line with the pattern of AD-associated neuronal death, whereas the association with cognitive test might account for residual cognitive functions. Show more

Keywords: Alzheimer’s disease, brain, flow cytometry, hippocampus, inflammation, Magnetic Resonance Imaging (MRI)

DOI: 10.3233/JAD-180250

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1131-1144, 2018

Authors: Cisternas, Pedro | Zolezzi, Juan M. | Lindsay, Carolina | Rivera, Daniela S. | Martinez, Alexis | Bozinovic, Francisco | Inestrosa, Nibaldo C.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-β (Aβ) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation …properties of its Aβ peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aβ peptide to aggregate in vitro . Then, we analyzed the age-dependent variation in soluble Aβ levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aβ was able to aggregate, forming fibrillar species in vitro . Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aβ levels and the Aβ42 /Aβ40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research. Show more

Keywords: Alzheimer’s disease, Aβ peptide, natural model, Octodon degus, senile plaques

DOI: 10.3233/JAD-180729

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1145-1163, 2018

Authors: Janssen, Niels | Handels, Ron L. | Sköldunger, Anders | Woods, Bob | Jelley, Hannah | Edwards, Rhiannon Tudor | Orrell, Martin | Selbæk, Geir | Røsvik, Janne | Gonçalves-Pereira, Manuel | Marques, Maria J. | Zanetti, Orazio | Portolani, Elisa | Irving, Kate | Hopper, Louise | Meyer, Gabriele | Bieber, Anja | Stephan, Astrid | Kerpershoek, Liselot | Wolfs, Claire A.G. | de Vugt, Marjolein E. | Verhey, Frans R.J. | Wimo, Anders | Consortium Actifcare

Article Type: Research Article

Abstract: Background: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed. Objective: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia. Methods: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one …unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items. Results: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for “company” was significantly related to lower total costs. Conclusion: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life. Show more

Keywords: Access to care, costs, dementia, quality of life, unmet needs, untimely

DOI: 10.3233/JAD-180531

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1165-1174, 2018

Authors: Jara-Moreno, Daniela | Castro-Torres, Rubn D. | Ettcheto, Miren | Auladell, Carme | Kogan, Marcelo J. | Folch, Jaume | Verdaguer, Ester | Cano, Amanda | Busquets, Oriol | Delporte, Carla | Camins, Antoni

Article Type: Research Article

Abstract: The most common type of dementia is Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) …of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology. Show more

Keywords: APPswe/PS1dE9, ethyl acetate extract, high fat diet, hippocampus, neuroinflammation, Ugni molinae

DOI: 10.3233/JAD-180174

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1175-1191, 2018

Authors: Porter, Tenielle | Burnham, Samantha C. | Milicic, Lidija | Savage, Greg | Maruff, Paul | Lim, Yen Ying | Li, Qiao-Xin | Ames, David | Masters, Colin L. | Rainey-Smith, Stephanie | Rowe, Christopher C. | Salvado, Olivier | Groth, David | Verdile, Giuseppe | Villemagne, Victor L. | Laws, Simon M. | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: With the exception of APOE, genetic variants associated with increased Alzheimer’s disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. Objective: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. Methods: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42 , total-tau, and phospho-tau, and decline in …cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer’s Cognitive Composite (PACC). Results: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh ) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype. Conclusions: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline. Show more

Keywords: Alzheimer’s disease, amyloid-β , cognitive decline, episodic memory, polygenic risk scores

DOI: 10.3233/JAD-180713

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1193-1211, 2018

Authors: Babulal, Ganesh M. | Chen, Suzie | Williams, Monique M. | Trani, Jean-Francois | Bakhshi, Parul | Chao, Grace L. | Stout, Sarah H. | Fagan, Anne M. | Benzinger, Tammie L.S. | Holtzman, David M. | Morris, John C. | Roe, Catherine M.

Article Type: Research Article

Abstract: Background: Symptomatic Alzheimer’s disease (AD) and depression independently increase crash risk. Additionally, depression is both a risk factor for and a consequence of AD. Objective: To examine whether a depression diagnosis, antidepressant use, and preclinical AD are associated with driving decline among cognitively normal older adults. Methods: Cognitively normal participants, age ≥65, were enrolled. Cox proportional hazards models evaluated whether a depression diagnosis, depressive symptoms (Geriatric Depression Scale), antidepressant use, cerebrospinal fluid (amyloid-β 42 [Aβ 42 ], tau, phosphorylated tau181 [ptau181 ]), and amyloid imaging biomarkers (Pittsburgh Compound B and Florbetapir) were associated with …time to receiving a rating of marginal/fail on a road test. Age was adjusted for in all models. Results: Data were available from 131 participants with age ranging from 65.4 to 88.2 years and mean follow up of 2.4 years (SD = 1.0). A depression diagnosis was associated with a faster time to receiving a marginal/fail rating on a road test and antidepressant use (p  = 0.024, HR = 2.62). Depression diagnosis and CSF and amyloid PET imaging biomarkers were associated with driving performance on the road test (p ≤0.05, HR = 2.51–3.15). In the CSF ptau181 model, depression diagnosis (p  = 0.031, HR = 2.51) and antidepressant use (p  = 0.037, HR = 2.50) were statistically significant predictors. There were no interaction effects between depression diagnosis, antidepressant use, and biomarker groups. Depressive symptomology was not a statistically significant predictor of driving performance. Conclusions: While, as previously shown, preclinical AD alone predicts a faster time to receiving a marginal/fail rating, these results suggest that also having a diagnosis of depression accelerates the onset of driving problems in cognitively normal older adults. Show more

Keywords: Alzheimer’s disease, antidepressants, biomarkers, depression, driving, older adults

DOI: 10.3233/JAD-180564

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1213-1221, 2018

Authors: Banks, Sarah J. | Zhuang, Xiaowei | Bayram, Ece | Bird, Chris | Cordes, Dietmar | Caldwell, Jessica Z.K. | Cummings, Jeffrey L. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Lateralization of default mode network (DMN) functioning has been shown to change with age. Similarly, lateralization of frontal lobe function has been shown to decline in age. The impact of amyloid pathology and the progression of Alzheimer’s disease (AD) on resting state lateralization has not been investigated. Due to the preferential involvement of the left hemisphere in verbal tasks, there may be a benefit to higher levels of left-lateralization in the performance of verbal memory tasks. Here we compared functional lateralization of the anterior and posterior DMN between four groups of participants: amyloid negative (Aβ-) and amyloid positive (Aβ+) groups …with normal cognition (NC), and Aβ+ groups with mild cognitive impairment (Aβ+MCI) or dementia (Aβ+AD). Differences were evident between groups in posterior DMN; the Aβ-NC group was more left-lateralized than both cognitively impaired Aβ+ groups. There was no difference in anterior DMN. No differences in overall network connectivity between groups were observed, suggesting that the functional lateralization finding is not secondary to general changes in connectivity. Left-lateralization of both networks was associated with better verbal recall performance. Older subjects, overall, had less left functional lateralization of the anterior DMN. Show more

Keywords: Alzheimer’s disease, amyloid-β, default mode network, resting state fMRI

DOI: 10.3233/JAD-180541

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1223-1234, 2018

Authors: Baghallab, Ibtisam | Reyes-Ruiz, Jorge Mauricio | Abulnaja, Khalid | Huwait, Etimad | Glabe, Charles

Article Type: Research Article

Abstract: The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aβ and the most widely used antibodies in Alzheimer’s disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1–16 and 17–24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4–10 while 4G8 maps to residues 18–23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the …minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5–7 of the Aβ target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera. Show more

Keywords: Amyloid antibodies, epitope mapping, epitopes, informatics, specificity

DOI: 10.3233/JAD-180582

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1235-1244, 2018

Authors: Zhang, Hanlin | Chen, Kang | Wang, Naili | Zhang, Di | Yang, Qian | Zhang, Qing | Liu, Pan | Wan, Mengyao | Gong, Changlin | Hong, Xinyu | Qiu, Wenying | Qian, Xiaojing | Chen, Yongmei | Ma, Chao

Article Type: Research Article

Abstract: The Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS/PUMC) Human Brain Bank was established in December 2012 and had accomplished 197 brain donations by November 2017. The brain bank was based on a large-scale willed body donation program in CAMS/PUMC starting from 1999. Demographic and medical characteristic analysis of brain donors was conducted to facilitate the construction of the brain bank. The average postmortem delay of brain donors was 17.7 h and 77.7% of these donors died less than 15 km away from the brain bank. Donors were predominantly with higher-level education (p  < 0.001) and at an older age …when registration (p  < 0.001) and donation (p  < 0.001) occurred. Our results elucidated the characteristics of donors in the CAMS/PUMC Human Brain Bank, which may provide useful information to target potential donors and improve the quality and quantity of brain specimens. The current study may pave the way for the construction of a nationwide network of standardized human brain banks in China. Show more

Keywords: Demography, tissue and organ procurement, tissue banks, tissue preservation

DOI: 10.3233/JAD-180779

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1245-1254, 2018

Authors: Gilbert, Thomas | Roche, Sylvain | Blond, Emilie | Bar, Jean-Yves | Drai, Jocelyne | Cuerq, Charlotte | Haution-Bitker, Marine | Ecochard, René | Bonnefoy, Marc

Article Type: Research Article

Abstract: Background: There is evidence that adipokines have roles in brain functioning and cognitive decline. Objective: Assess the role of leptin and adiponectin levels in predicting changes in neuro-cognitive disorders (NCD). Methods: The study included 205 patients over 65 years of age presenting for a one-day hospitalization for current assessment of cognitive function. Peripheral blood leptin and adiponectin levels were measured at admission. Demographic variables, body mass index (BMI), and history of hypertension were also recorded. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at admission and at later scheduled visits over a median follow-up …period of 14.5 months. Conventional univariate comparisons were made between diagnosis groups (Alzheimer’s disease (AD), mild NCD, vascular/mixed dementia). Changes in MMSE scores over time were examined with regard to the above variables using a linear mixed model. Results: The mean BMI was significantly lower (by 2 kg/m2 , p  = 0.01) in patients with AD than in patients with either mild-NCD or vascular/mixed dementia. Leptin levels were significantly higher (p  = 0.043) and adiponectin levels significantly lower (p  = 0.045) in patients with mild-NCD than in patients with major-NCD (AD or vascular/mixed dementia). However, the mixed model suggested no influence of the baseline levels of these two biomarkers on the course of cognitive decline. Conclusion: The present study confirms the associations between leptin and adiponectin and AD or AD-related disorders but did not confirm that these peptides may be used as predictive biomarkers of cognitive decline. Show more

Keywords: Adiponectin, alzheimer’s disease, body composition, dementia, leptin

DOI: 10.3233/JAD-180533

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1255-1264, 2018