Journal of Alzheimer's Disease - Volume 59, issue 3

Authors: Giil, Lasse M. | Vedeler, Christian A. | Kristoffersen, Einar K. | Nordrehaug, Jan Erik | Heidecke, Harald | Dechend, Ralf | Schulze-Forster, Kai | Muller, Dominik N. | von Goetze, Victoria S. | Cabral-Marques, Otavio | Riemekasten, Gabriela | Vogelsang, Petra | Nygaard, Staale | Lund, Anders | Aarsland, Dag

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with several antibodies as well as signaling molecules and receptors. These may be detrimental in the presence of a disrupted blood-brain barrier (BBB). Objective: To investigate whether the levels of antibodies toward 33 signaling molecules involved in neurotransmitter, vascular, and immune functions were associated with AD and, within the AD group; cognitive function and mood. Methods: Antibodies in sera from patients with mild AD [(n  = 91) defined as a Mini-Mental State Examination ≥ 20 or a Clinical Dementia Rating Scale≤1] and healthy controls (n  = 102) were measured with enzyme-linked immunosorbent …assays. Levels in AD and controls were compared by Mann-Whitney test. In the AD group, associations between antibodies and psychometric test scores were analyzed by robust regression. The false discovery threshold was set to 0.05. Results: Antibodies to serotonin receptors [5-HT2A R (effect size (r)  = 0.21, p  = 0.004), 5-HT2C R (r  = 0.25, p  = 0.0005) and 5-HT7 R (r  = 0.21, p  = 0.003)], vascular endothelial growth factor receptor 1 [VEGFR1 (r  = 0.29, p  < 0.001)] and immune-receptors (Stabilin-1 (r  = 0.23, p  = 0.001) and C5aR1 (r  = 0.21, p  = 0.004) were higher in AD. Psychomotor speed was associated with D1 R-abs (β 0.49, p  < 0.001), depression with ETAR-abs (β 0.31, p  < 0.001), and visuospatial function with 5-HT1A R-abs (β 0.27, p  = 0.004) despite similar antibody levels compared to controls. Conclusions: Antibody levels to VEGFR1, serotonergic receptors, and receptors in the immune system were increased in AD. Antibodies at similar levels as in controls were associated cognitive dysfunction and depression in AD. Show more

Keywords: C5aR, 5-HT2AR, 5-HT2CR, 5-HT7R, MADRS, naturally occurring antibodies, Stablin-1, Trail Making A, VEGFR1, VOSP

DOI: 10.3233/JAD-170245

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 929-939, 2017

Authors: Chen, Jia | Zhang, Tao | Jiao, Shusheng | Zhou, Xinfu | Zhong, Jinhua | Wang, Yanjiang | Liu, Juan | Deng, Juan | Wang, Shuiping | Xu, Zhiqiang

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is pathologically known for the amyloid-β (Aβ) deposition, neurofibrillary tangles, and neuronal loss in the brain. The precursor of brain-derived neurotrophic factor (proBDNF) before proteolysis has opposing functions to its mature form in neuronal survival and neurite growth. However, the role of proBDNF in the pathogenesis of AD remains unclear. Objective: To investigate the effects of proBDNF on neurons in vitro , and on learning and memory impairment and brain Aβ production in a transgenic AD mouse model (APPswePS1dE9). Methods: We here examined the effects of proBDNF on the viability (MTT assay) …and neurite growth (morphologic measurement) of the primary neurons in vitro . After the intracerebroventricular injection of adeno-associated virus-proBDNF (AAV-proBDNF), we then investigated the learning and memory impairment (Morris water maze) and Aβ deposition in the brains of the AD mice. Results: The results showed that proBDNF could inhibit neuronal viability and neurite growth in vitro , enhance Aβ levels, and accelerate its deposition in the brain, which was consistent with the learning and memory impairment of AD mice, likely dependent on the membrane receptor of p75NTR. Conclusions: Our findings suggest that proBDNF may exert a crucially negative effect during AD pathogenesis andprogression. Show more

Keywords: Alzheimer’s disease, amyloid-β, learning and memory, neurotoxicity, p75NTR, proBDNF

DOI: 10.3233/JAD-161191

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 941-949, 2017

Authors: Niwa, Atsushi | Ii, Yuichiro | Shindo, Akihiro | Matsuo, Ko | Ishikawa, Hidehiro | Taniguchi, Akira | Takase, Shinichi | Maeda, Masayuki | Sakuma, Hajime | Akatsu, Hiroyasu | Hashizume, Yoshio | Tomimoto, Hidekazu

Article Type: Research Article

Abstract: Microvascular lesions including cortical microinfarctions (CMIs) and cerebral lobar microbleeds (CMBs) are usually caused by cerebral amyloid angiopathy (CAA) in the elderly and are correlated with cognitive decline. However, their radiological-histopathological coincidence has not been revealed systematically with widely used 3-Tesla (3T) magnetic resonance imaging (MRI). The purpose of the present study is to delineate the histopathological background corresponding to MR images of these lesions. We examined formalin-fixed 10-mm thick coronal brain blocks from 10 CAA patients (five were also diagnosed with Alzheimer’s disease, three with dementia with Lewy bodies, and two with CAA only) with dementia and six non …CAA patients with neurodegenerative disease. Using 3T MRI, both 3D-fluid attenuated inversion recovery (FLAIR) and 3D-double inversion recovery (DIR) were examined to identify CMIs, and T2* and susceptibility-weighted images (SWI) were examined to identify CMBs. These blocks were subsequently examined histologically and immunohistochemically. In CAA patients, 48 CMIs and 6 lobar CMBs were invariably observed in close proximity to degenerated Aβ-positive blood vessels. Moreover, 16 CMIs (33%) of 48 were detected with postmortem MRI, but none were seen when the lesion size was smaller than 1 mm. In contrast, only 1 undeniable CMI was founded with MRI and histopathology in 6 non CAA patients. Small, cortical high-intensity lesions seen on 3D-FLAIR and 3D-DIR images likely represent CMIs, and low-intensity lesions in T2* and SWI correspond to CMBs with in vivo MRI. Furthermore, a close association between amyloid-laden vessels and these microvascular lesions indicated the contribution of CAA to their pathogenesis. Show more

Keywords: Autopsy, bleeding, cerebral amyloid angiopathy, dementia, infarct, magnetic resonance imaging, pathology

DOI: 10.3233/JAD-161242

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 951-959, 2017

Authors: Vaz, Gustavo Richter | Hädrich, Gabriela | Bidone, Juliana | Rodrigues, Jamile Lima | Falkembach, Mariana Corrêa | Putaux, Jean-Luc | Hort, Mariana Appel | Monserrat, José Maria | Varela Junior, Antônio Sergio | Teixeira, Helder Ferreira | Muccillo-Baisch, Ana Luiza | Horn, Ana Paula | Dora, Cristiana Lima

Article Type: Research Article

Abstract: Background: Curcumin (CUR) has properties that can be useful for the treatment of Alzheimer’s disease. Such properties are the inhibition of amyloid-β-protein (Aβ) aggregation, Aβ-induced inflammation, and activities of β-secretase and acetylcholinesterase. However, previous studies have revealed that CUR exhibited low bioavailability and difficulties in reaching the brain. Objective: To overcome such drawbacks, this study aims at developing nasal lipid nanocarriers loaded with CUR to effectively target the brain. Methods: The lipid nanocarriers (NE) were prepared using the hot solvent diffusion associated with the phase inversion temperature methods. Physico-chemical and morphological characterizations and in vitro …drug release of the nanocarriers were carried out. The CUR permeation/retention was analyzed in Franz-type diffusion cell using porcine nasal mucosa. Confocal laser scan and histopathological studies were also performed. Results: The results showed that the NE sizes ranged between 18 nm and 44 nm with negative zeta potential. The CUR content ranged from 0.24 to 1.50 mg/mL with an encapsulation efficiency of 99%. The profiles of CUR release indicated a biphasic kinetics. CUR-NE permeation across the porcine nasal mucosa was higher when compared to free CUR. These results have also been validated through an analysis on a confocal microscopy. In addition, no toxicity on the nasal mucosa has been observed in a histopathological analysis. Conclusion: These results suggest that it is possible to develop NEs with a high content of CUR and small particle size. Such an encapsulation increases the potential of CUR permeation across the porcine nasal mucosa. Show more

Keywords: Antioxidant, brain targeting, curcumin, degenerative diseases, diffusion cell Franz-type, intranasal route, lipid nanocarrier

DOI: 10.3233/JAD-160355

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 961-974, 2017

Authors: Gatchel, Jennifer R. | Donovan, Nancy J. | Locascio, Joseph J. | Schultz, Aaron P. | Becker, J. Alex | Chhatwal, Jasmeer | Papp, Kathryn V. | Amariglio, Rebecca E. | Rentz, Dorene M. | Blacker, Deborah | Sperling, Reisa A. | Johnson, Keith A. | Marshall, Gad A.

Article Type: Research Article

Abstract: Background: Depressive symptoms are common in older adults and associated with increased morbidity and cognitive decline. These symptoms occur during preclinical and prodromal stages of Alzheimer’s disease (AD), but their relationship to tau, one of the main AD proteinopathies, is poorly understood. Objective: The objective of this study was to investigate the cross-sectional association between depressive symptoms and cerebral tau [18 F T807 (also known as 18 F-AV-1451) tau positron emission tomography (PET) imaging] in cognitively normal (CN) older adults. Methods: We measured depressive symptoms using the Geriatric Depression Scale (GDS), and in vivo cerebral …tau using T807 PET in 111 CN older adults. We employed general linear regression models to evaluate the relationship of GDS score regressed on entorhinal cortex (EC) or inferior temporal (IT) tau in separate backward elimination models. Other predictors included age, sex, and in secondary analyses, amyloid (Pittsburgh Compound B PET). Results: Higher GDS was significantly associated with greater IT tau (partial r  = 0.188, p  = 0.050) and marginally associated with greater EC tau (partial r  = 0.183, p  = 0.055). In additional analyses including both linear and quadratic age terms, we found a significant U-shaped relation of GDS to age (p  = 0.001). Conclusions: Results suggest that IT and EC tau are modestly associated with depressive symptoms in CN older adults. Findings suggest a link between depressive symptoms and tau-mediated neurodegeneration in a region vulnerable in AD. Future longitudinal studies examining the association of more severe depressive symptoms and cerebral tau accumulation are needed to substantiate this finding and to guide prevention and treatment in AD. Show more

Keywords: Alzheimer’s disease, amyloid, cognitively normal, depression, depressive symptoms, positron emission tomography, tau

DOI: 10.3233/JAD-170001

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 975-985, 2017

Authors: Jiang, Julie M. | Seng, Elizabeth K. | Zimmerman, Molly E. | Sliwinski, Martin | Kim, Mimi | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: The Perceived Stress Scale (PSS) is made up of two subscales but is typically used as a single summary measure. However, research has shown that the two subscales may have differential properties in older adults. Objective: To evaluate the internal consistency, test-retest reliability, and the concurrent and predictive validity for development of amnestic mild cognitive impairment (aMCI) of the positively-worded (PSS-PW) and negatively-worded (PSS-NW) subscale scores of the PSS in older adults. Methods: We recruited community residing older adults free of dementia from the Einstein Aging Study. Reliability of the PSS-PW and PSS-NW was assessed …using Cronbach’s alpha for internal consistency and intraclass correlation for one year test-retest reliability. Concurrent validity was evaluated by examining the relationship between the PSS subscales and depression, anxiety, neuroticism, and positive and negative affect. Predictive validity was assessed using multivariate Cox regression analyses to examine the relationship between baseline PSS-PW and PSS-NW score and subsequent onset of aMCI. Results: Both PSS-PW and PSS-NW showed adequate internal consistency and retest reliabilities. Both the PSS-PW and PSS-NW were associated with depression, neuroticism, and negative affect. The PSS-NW was uniquely associated with anxiety while the PSS-PW was uniquely associated with positive affect. Only the PSS-PW was associated with a statistically significant increased risk of incident aMCI (HR = 1.27; 95% CI: 1.06–1.51 for every 5-point increase in PSS-PW). Conclusions: Evaluating the separate effects of the two PSS subscales may reveal more information than simply using a single summation score. Future research should investigate the PSS-PW and PSS-NW as separate subscales. Show more

Keywords: Adult, cognitive dysfunction, cohort study, dementia, reproducibility of results, psychological stress

DOI: 10.3233/JAD-170289

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 987-996, 2017

Authors: Turró-Garriga, Oriol | Calvó-Perxas, Laia | Vilalta-Franch, Joan | Hernández-Ferrándiz, Marta | Flaqué, Margarita | Linares, Marta | Cullell, Marta | Gich, Jordi | Casas, Isabel | Perkal, Héctor | Garre-Olmo, Josep | on behalf of the Registry of Dementia of Girona Study Group (ReDeGi Study Group)

Article Type: Research Article

Abstract: Background: There are several position statements and clinical practice guidelines (CPG) for diagnosing dementia. Objective: Our aims were to evaluate the adherence to CPG among specialists in the 7 memory clinics included in the Registry of Dementias of Girona (ReDeGi), and to compare the results between 2007–2011 and 2012–2015. We also determined the time and number of visits required to achieve a diagnosis, the supplementary tests ordered, and the drugs prescribed according to dementia subtypes. Methods: Medical charts of a stratified random sample of 475 ReDeGi cases were reviewed. Basic dementia work-up was evaluated using as …a reference evidence-based CPG. An Index of Adherence (AI) was calculated using the following items in the medical chart: cognitive symptomatology; functional disability evaluation; physical examination; neurological examination; psychiatric examination; brief cognitive examination; activities of daily living performance examination; blood test; structural neuroimaging (CT-scan or MRI). Results: The mean AI to CPG among specialists was of 8.2 points, and it improved from 7.9 points in 2007–2011 to 8.5 points in 2012–2015 (Cohen’s d  = 0.46). A lower adherence was detected in the most severe cases. A dementia diagnosis required 3.5 visits, regardless of the subtype of dementia, although milder cases required more time, more visits, and more supplementary tests than severe cases. Conclusion: The adherence to CPG in the catchment area of the ReDeGi is high, and an epidemiological surveillance system such as the ReDeGi may help in improving it. Dementia guidelines should establish procedures adapted to clinical practice, with simplified recommendations for most severe cases. Show more

Keywords: Dementia, diagnosis, practice guideline, registries

DOI: 10.3233/JAD-170284

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 997-1007, 2017

Authors: Bussè, Cinzia | Anselmi, Pasquale | Pompanin, Sara | Zorzi, Giovanni | Fragiacomo, Federica | Camporese, Giulia | Di Bernardo, Gian Antonio | Semenza, Carlo | Caffarra, Paolo | Cagnin, Annachiara

Article Type: Research Article

Abstract: Background: Standard measures of commonly used memory tests may not be appropriate to distinguish different neurodegenerative diseases affecting memory. Objective: To study whether specific measures of verbal memory obtained with the Rey Auditory Verbal Learning test (RAVLT) could help distinguish dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD). Methods: Twenty-nine DLB and 32 AD patients participated in the study and were followed longitudinally for 3 years until the diagnosis was confirmed according to standard clinical criteria. Twenty-eight healthy elderly subjects served as controls. The following verbal memory measures were evaluated: verbal learning (VL), verbal forgetting …(VF), percentage of verbal forgetting (VF%), and serial position effects of the immediate recall performance. Results: DLB and AD groups have comparable performances at the RAVLT immediate and delayed recall tasks. However, VL was higher in DLB than AD while VF% was greater in AD. With a VF% cut-off ≥75%, AD and DLB patients were differently distributed, with 58% of AD versus 21% of DLB above this cut-off. The recency effect was significant higher in AD than DLB. Discussion: DLB patients had a better performance in VL than AD, but worse VF and recency effect. These specific measures of verbal memory could be used as cognitive markers in the differential diagnosis between these two conditions. Show more

Keywords: Alzheimer’s disease, cognitive assessment, Lewy body disease, memory

DOI: 10.3233/JAD-170154

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1009-1015, 2017

Authors: Johansson, Per | Almqvist, Erik G. | Bjerke, Maria | Wallin, Anders | Johansson, Jan-Ove | Andreasson, Ulf | Blennow, Kaj | Zetterberg, Henrik | Svensson, Johan

Article Type: Research Article

Abstract: Background: Apolipoprotein E (ApoE) has been extensively studied in Alzheimer’s disease (AD), but little is known of apolipoprotein A-I (ApoA-I) in cerebrospinal fluid (CSF). Objective: Plasma lipids as well as ApoA-I and ApoE in plasma and CSF were determined and related to Mini-Mental State Examination (MMSE) score, APOE genotype, and CSF AD biomarkers. Methods: Consecutive patients with AD (n  = 29), stable mild cognitive impairment (n  = 13), other dementias (n  = 14), and healthy controls (n  = 18) were included at a single center. Results: AD patients had higher plasma triglycerides and lower CSF ApoA-I concentration …than controls (both p  < 0.05). CSF ApoE concentration was reduced in other dementias (p  < 0.01). In AD as well as other dementias, the ratios between CSF and plasma concentrations of both ApoA-I and ApoE were lower than those in the controls. ApoA-I and ApoE in plasma and CSF were not influenced by APOE ɛ 4 allele distribution. In the total study population (n  = 74), CSF ApoA-I correlated positively with MMSE score (r  = 0.26, p  < 0.05) and negatively with CSF P-tau (r  = –0.25, p  < 0.05). CSF ApoE correlated positively with CSF concentrations of T-tau and P-tau in the total study population and in AD patients. Conclusion: CSF ApoA-I was reduced in AD patients and associated with measures of cognitive function and AD disease status. The mechanisms underlying the decreased CSF:plasma ratios of ApoA-I and ApoE in AD and other dementias need to be explored in further studies. Show more

Keywords: Alzheimer’s disease, apolipoprotein A-I, apolipoprotein E, cerebrospinal fluid, lipids, other dementia

DOI: 10.3233/JAD-170226

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1017-1026, 2017

Authors: Price, Catherine C. | Garvan, Cynthia | Hizel, Loren P. | Lopez, Marcos G. | Billings IV, Frederic T.

Article Type: Research Article

Abstract: Background: Reduced preoperative cognition is a risk factor for postoperative delirium. The significance for type of preoperative cognitive deficit, however, has yet to be explored and could provide important insights into mechanisms and prediction of delirium. Objective: Our goal was to determine if certain cognitive domains from the general cognitive screener, the Mini-Mental State Exam (MMSE), predict delirium after cardiac surgery. Methods: Patients completed a preoperative MMSE prior to undergoing elective cardiac surgery. Following surgery, delirium was assessed throughout ICU stay using the Confusion Assessment Method for ICU delirium and the Richmond Agitation and Sedation …Scale. Results: Cardiac surgery patients who developed delirium (n  = 137) had lower total MMSE scores than patients who did not develop delirium (n  = 457). In particular, orientation to place, working memory, delayed recall, and language domain scores were lower. Of these, only the working memory and delayed recall domains predicted delirium in a regression model adjusting for history of chronic obstructive pulmonary disease, age, sex, and duration of cardiopulmonary bypass. For each word not recalled on the three-word delayed recall assessment, the odds of delirium increased by 50%. For each item missed on the working memory index, the odds of delirium increased by 36%. Of the patients who developed delirium, 47% had a primary impairment in memory, 21% in working memory, and 33% in both domains. The area under the receiver operating characteristics curve using only the working memory and delayed recall domains was 0.75, compared to 0.76 for total MMSE score. Conclusion: Delirium risk is greater for individuals with reduced MMSE scores on the delayed recall and working memory domains. Research should address why patients with memory and executive vulnerabilities are more prone to postoperative delirium than those with other cognitive limitations. Show more

Keywords: Alzheimer’s disease, cardiovascular surgical procedures, cognition, cognitive dysfunction, confusion, dementia, screening, thoracic surgery

DOI: 10.3233/JAD-170380

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1027-1035, 2017

Authors: Shi, Yachen | Gu, Lihua | Alsharif, Abdul Azeez | Zhang, Zhijun

Article Type: Research Article

Abstract: To systematically assess the clinical significance of platelet amyloid-β protein precursor (AβPP) ratio between Alzheimer’s disease (AD) patients and controls. 14 articles were selected in this analysis by search of databases including PubMed and Web of Science up to December 2016. Random effects models were used to calculate the standardized mean difference (SMD). Subgroup analyses were used to detect the cause of heterogeneity. The result showed a significant drop in platelet AβPP ratio in AD patients compared to controls [SMD: –1.871; 95% CI: (–2.33, –1.41); p  < 0.001; I2  = 88.0% ]. Subgroup analysis revealed races or the quality of studies may …be the cause of high heterogeneity. This meta-analysis concluded that there is a close association between platelet AβPP ratio and AD. It is necessary to design a sizable sample study to further support that platelet AβPP ratio can be a biomarker of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β precursor protein, biomarker, meta-analysis, platelet

DOI: 10.3233/JAD-170253

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1037-1044, 2017

Authors: Kodamullil, Alpha Tom | Iyappan, Anandhi | Karki, Reagon | Madan, Sumit | Younesi, Erfan | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Perturbance in inflammatory pathways have been identified as one of the major factors which leads to neurodegenerative diseases (NDD). Owing to the limited access of human brain tissues and the immense complexity of the brain, animal models, specifically mouse models, play a key role in advancing the NDD field. However, many of these mouse models fail to reproduce the clinical manifestations and end points of the disease. NDD drugs, which passed the efficacy test in mice, were repeatedly not successful in clinical trials. There are numerous studies which are supporting and opposing the applicability of mouse models in neuroinflammation and …NDD. In this paper, we assessed to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level. Based on our mechanistic modeling approach, we investigate the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species. Show more

Keywords: Alzheimer’s disease, human, mice, neuroinflammation

DOI: 10.3233/JAD-170255

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1045-1055, 2017

Authors: Santos, Cláudia Y. | Machan, Jason T. | Wu, Wen-Chih | Snyder, Peter J.

Article Type: Research Article

Abstract: To explore early autonomic cardiac changes in pre-clinical Alzheimer’s disease (AD), we have evaluated electrocardiologic measures of vagal tone for 63 adults (ages 55–75) at rest, during cognitive testing, and then again at rest. All subjects had multiple risk factors for AD, and all completed amyloid PET scans (18 F-Florbetapir) to determine amyloid positivity (Aβ+). No change in electrocardiographic measures were observed for Aβ+ participants under each testing condition, whereas Aβ–subjects showed an expected increase in vagal tone during the cognitive stress condition. These findings suggest an early relationship between cortical Aβ accumulation, a precursor to AD development, and autonomic …cardiac function. Show more

Keywords: Aging, Alzheimer’s disease, cardiac, heart rate variability, resting sinus arrhythmia, vagal tone

DOI: 10.3233/JAD-170217

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1057-1065, 2017

Authors: Wu, Meina | Shi, Hui | He, Yexin | Yuan, Li | Qu, Xuesong | Zhang, Jun | Wang, Zhaojun | Cai, Hongyan | Qi, Jinshun

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia, and effective therapeutics are lacking. Colivelin (CLN), a novel, strong humanin derivative, is effective in vitro in preventing cell death induced by AD-causative genes and amyloid-β protein (Aβ) even at a low concentration. We recently demonstrated that intrahippocampal injection of CLN prevents Aβ25–35 -induced deficits in spatial memory and synaptic plasticity in normal rats. Here, we further observed the effects of chronically intranasally (i.n.) administered CLN on cognitive behaviors and pathological hallmarks in 9-month-old APPswe/PS1dE9 (APP/PS1) AD mice using multiple behavioral tests and immunochemistry. The electrophysiological mechanism of CLN …neuroprotection was also investigated by recording in vivo hippocampal long-term potentiation (LTP). CLN pretreatment effectively prevented impairments in new object recognition, working memory, and long-term spatial memory and reversed the depression of in vivo hippocampal LTP in APP/PS1 mice. Additionally, chronic application of CLN obviously reduced Aβ deposition in the hippocampus in APP/PS1 mice. These results indicate that CLN has strong neuroprotective effects on learning and memory behaviors in APP/PS1 mice and that this behavioral improvement is closely associated with the reduction of Aβ deposition and alleviation of LTP suppression in the hippocampus, supporting the potential of CLN for the prevention and treatment of AD. Show more

Keywords: Amyloid-β protein, APP/PS1 transgenic mice, colivelin, learning and memory, long-term potentiation

DOI: 10.3233/JAD-170307

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1067-1078, 2017

Authors: Esquerda-Canals, Gisela | Martí-Clúa, Joaquim | Roda, Alejandro R. | Villegas, Sandra

Article Type: Research Article

Abstract: The main histopathological hallmarks of Alzheimer’s disease (AD) are the extracellular deposition of neuritic amyloid plaques, composed of amyloid-β (Aβ) peptide, and the intracellular accumulation of neurofibrillary tangles, composed of hyperphosphorylated tau. Both traits are emulated in the 3xTg-AD mouse model. Because the relevance of this model in the bibliography and the main role of Aβ in neuronal impairment, here we have detailed the brain Aβ/AβPP distribution to subsequently quantify cellular density and intracellular burden for specific neuronal populations in the early stages of the disease. 6E10 immunoreactivity was evident in the deep layers of the cerebral cortex, in the …pyramidal cell layer of the hippocampus, in the basolateral amygdala nucleus, and in the deep cerebellar nuclei macroneurons; whereas the specific neuronal populations with decreased cellular density were the large pyramidal neurons from the layers V-VI in the cerebral cortex, the pyramidal neurons from the CA2-3 region in the hippocampus, and the large neurons from the basolateral nucleus in the amygdala, apart from the already reported deep cerebellar nuclei. Interestingly, we found a strong correlation between intracellular Aβ/AβPP burden and cellular density in all these populations. In addition, behavioral testing showed the functional consequences of such a neuronal depletion. Concretely, anxious-like behavior is manifested in the corner and open-field tests, as well as cognitive functions shown to be impaired in the novel object recognition test and Morris water maze paradigm. To our knowledge, this is the first deep characterization of the specific neuronal populations affected in the 3xTg-AD mouse model. Show more

Keywords: 3xTg-AD, Alzheimer’s disease, amyloid-β, AβPP, behavioral alterations, 6E10 immunoreactivity, neuronal loss

DOI: 10.3233/JAD-170218

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1079-1096, 2017

Authors: Küster, Olivia C. | Laptinskaya, Daria | Fissler, Patrick | Schnack, Cathrin | Zügel, Martina | Nold, Verena | Thurm, Franka | Pleiner, Sina | Karabatsiakis, Alexander | von Einem, Björn | Weydt, Patrick | Liesener, André | Borta, Andreas | Woll, Alexander | Hengerer, Bastian | Kolassa, Iris-Tatjana | von Arnim, Christine A.F.

Article Type: Research Article

Abstract:  Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and …social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings. Show more

Keywords: Brain-derived neurotrophic factor, cognitive function, dementia, exercise training, kynurenine, lifestyle∥

DOI: 10.3233/JAD-170447

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1097-1111, 2017

Authors: Edwards, Jodi D. | Ramirez, Joel | Callahan, Brandy L. | Tobe, Sheldon W. | Oh, Paul | Berezuk, Courtney | Lanctôt, Krista | Swardfager, Walter | Nestor, Sean | Kiss, Alexander | Strother, Stephen | Black, Sandra E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Hypertension is an important risk factor for Alzheimer’s disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid. Objective: The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication. Methods: We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer’s Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal …fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition. Results: Individuals treated with ARBs showed larger hippocampal volumes (R2  = 0.83, p  = 0.05) and brain parenchymal fraction (R2  = 0.83, p  = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2  = 0.83, p  = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p  < 0.05). Conclusions: Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD. Show more

Keywords: Alzheimer’s disease, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, hypertension, white matter hyperintensities

DOI: 10.3233/JAD-170238

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1113-1122, 2017

Authors: Sinclair, Lindsey I. | Love, Seth

Article Type: Research Article

Abstract: Background: Possession of APOE ɛ 4 is a strong risk factor for late-onset Alzheimer’s disease and is associated with loss of synaptic proteins in the elderly even in the absence of Alzheimer’s disease. Objective: We hypothesized that ɛ 4 allele possession in non-demented adults aged under-75 would also be associated with alterations in the levels of synaptic proteins. Methods: We measured synaptophysin, PSD95, drebrin, SNAP-25, and septin 7 by ELISA in hippocampus and superior temporal gyrus from 103 adults aged <75 without dementia. Corresponding gene expression was measured by RT-PCR. Results: There was no …evidence that ɛ 4 affected levels of the proteins measured. Instead we found an increase in post-synaptic proteins in the hippocampi of those with an ɛ 32 genotype. The evidence was strongest for drebrin (p  = 0.011). There was some evidence of increased synaptic protein gene expression in ɛ 4 carriers. Conclusions: People with an APOE ɛ 32 genotype have a reduced risk of Alzheimer’s disease. It may be relevant that they have a higher level of post-synaptic proteins in the hippocampus even in earlier adulthood. Show more

Keywords: Alzheimer’s disease, APOE, dementia, drebrin, genetics, postmortem tissue, PSD-95, synaptic proteins, synaptophysin

DOI: 10.3233/JAD-170316

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1123-1137, 2017