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