Journal of Alzheimer's Disease - Volume 51, issue 1

Authors: Racine, Eric | Forlini, Cynthia | Aspler, John | Chandler, Jennifer

Article Type: Review Article

Abstract: Preclinical Alzheimer’s disease (AD), a newly proposed, actively researched, and hotly debated research-only diagnostic category, raises the prospect of an ethical dilemma: whether, and possibly how, to treat a disorder with no target symptoms. This proposed category rests on the detection of a number of biomarkers thought to provide evidence of AD pathophysiology years before any behavioral symptoms manifest. Faced with limited treatment options, patients and their relatives may come to consider complementary and alternative medicine (CAM) a viable option, albeit one with minimal supporting evidence. Accordingly, the hopes and needs of some preclinical patients and their relatives could further …fuel market-oriented entrepreneurship for CAM. In this ethics review, we provide background and reflect on some ethical questions related to the roles of key stakeholders arising from the potential for CAM use in the context of a possible preclinical AD diagnosis. Show more

Keywords: Alzheimer’s disease, bioethics, complementary therapies, health policy

DOI: 10.3233/JAD-150534

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 1-9, 2016

Authors: Robillard, Julie M.

Article Type: Research Article

Abstract: Racine et al.’s Ethics Review highlights the challenges associated with the use of complementary and alternative medicine (CAM) in the context of early diagnosis of Alzheimer’s disease (AD). As CAM are increasingly promoted and sold on the Internet, the unregulated online environment has the potential to significantly impact the health and well-being of the aging demographic, and in particular of individuals concerned about AD. In this response, the ethical challenges specific to the online environment are discussed and solutions are put forward to empower the aging population to maximize the benefits of the online environment while minimizing the potential harms …of misinformation, conflict of interest, and other ethical concerns. Show more

Keywords: Alzheimer’s disease, bioethics, complementary therapies, health policy

DOI: 10.3233/JAD-150641

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 11-13, 2016

Authors: Shelef, Assaf | Barak, Yoram | Berger, Uri | Paleacu, Diana | Tadger, Shelly | Plopsky, Igor | Baruch, Yehuda

Article Type: Short Communication

Abstract: Background: Tetrahydrocannabinol (THC) is a potential treatment for Alzheimer’s disease (AD). Objective: To measure efficacy and safety of medical cannabis oil (MCO) containing THC as an add-on to pharmacotherapy, in relieving behavioral and psychological symptoms of dementia (BPSD). Methods: Eleven AD patients were recruited to an open label, 4 weeks, prospective trial. Results: Ten patients completed the trial. Significant reduction in CGI severity score (6.5 to 5.7; p  <  0.01) and NPI score were recorded (44.4 to 12.8; p  <  0.01). NPI domains of significant decrease were: Delusions, agitation/aggression, irritability, apathy, sleep and caregiver …distress. Conclusion: Adding MCO to AD patients’ pharmacotherapy is safe and a promising treatment option. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, cannabis, tetrahydrocannabinol

DOI: 10.3233/JAD-150915

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 15-19, 2016

Authors: Leinonen, Henri | Lipponen, Arto | Gurevicius, Kestutis | Tanila, Heikki

Article Type: Short Communication

Abstract: Alzheimer’s disease has been shown to affect vision in human patients and animal models. This may pose the risk of bias in behavior studies and therefore requires comprehensive investigation. We recorded electroretinography (ERG) under isoflurane anesthesia and visual evoked potentials (VEP) in awake amyloid expressing AβPPswe/PS1dE9 (AβPP/PS1) and wild-type littermate mice at a symptomatic age. The VEPs in response to patterned stimuli were normal in AβPP/PS1 mice. They also showed normal ERG amplitude but slightly shortened ERG latency in dark-adapted conditions. Our results indicate subtle changes in visual processing in aged male AβPP/PS1 mice specifically at a retinal level.

Keywords: Alzheimer disease, amyloid-beta, animal models, electroretinography, vision, visual evoked potentials

DOI: 10.3233/JAD-150798

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 21-26, 2016

Authors: Caffarra, Paolo | Ghetti, Caterina | Ruffini, Livia | Spallazzi, Marco | Spotti, Annamaria | Barocco, Federica | Guzzo, Caterina | Marchi, Massimo | Gardini, Simona

Article Type: Short Communication

Abstract: Free and Cued Selective Reminding Test (FCSRT) measures immediate and delayed episodic memory and cueing sensitivity and is suitable to detect prodromal Alzheimer’s disease (AD). The present study aimed at investigating the segregation effect of FCSRT scores on brain metabolism of memory-related structures, usually affected by AD pathology, in the Mild Cognitive Impairment (MCI) stage. A cohort of forty-eight MCI patients underwent FCSRT and 18 F-FDG-PET. Multiple regression analysis showed that Immediate Free Recall correlated with brain metabolism in the bilateral anterior cingulate and delayed free recall with the left anterior cingulate and medial frontal gyrus, whereas semantic cueing sensitivity …with the left posterior cingulate. FCSRT in MCI is associated with neuro-functional activity of specific regions of memory-related structures connected to hippocampal formation, such as the cingulate cortex, usually damaged in AD. Show more

Keywords: Alzheimer’s disease, FDG-PET, Free and Cued Selective Reminding Test, medial-temporal structures, mild cognitive impairment

DOI: 10.3233/JAD-150418

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 27-31, 2016

Authors: Yang, Cui-cui | Kuai, Xue-xian | Gao, Wen-bin | Yu, Jian-chun | Wang, Qi | Li, Lin | Zhang, Lan

Article Type: Research Article

Abstract: Background: An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer’s disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD. Objective: To investigate the effects of morroniside (MOR), isolated from Cornus officinalis , on tau hyperphosphorylation and its underlying mechanisms related to PP2A. Methods: SK-N-SH cells were pretreated with 50–200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h. PP2Ac siRNA was transfected into HEK293 cells to determine the direct interaction of MOR with PP2A. Western blotting was used to measure the expression …of proteins and enzymes. PP2A activity was measured by molybdenum blue spectrophotometry. Results: Pretreatment with MOR improved the cellular morphological damage and inhibited tau hyperphosphorylation in SK-N-SH cells induced by OA, a PP2A inhibitor. Moreover, MOR increased PP2A activity, concurrent with a decrease in the expression of demethylated PP2A at Leu309 and phosphorylated PP2A at Tyr307. MOR decreased protein phosphatase methylesterase 1 (PME-1) expression and the ratio of PME-1/leucine carboxyl methyltransferase 1 (LCMT-1). Furthermore, MOR treatment decreased the phosphorylation of Src at Tyr416, which regulates the phosphorylation of PP2A. MOR had no effect on PP2Ac expression and tau hyperphosphorylation in PP2Ac siRNA-transfected cells. Conclusion: MOR attenuated OA-induced tau hyperphosphorylation via PP2A activation, and its mechanism might be related to the regulation of PP2Ac post-translational modification and upstream enzymes such as Src and PME-1. Show more

Keywords: Alzheimer’s disease, morroniside, okadaic acid, protein phosphatase-2A, tau hyperphosphorylation

DOI: 10.3233/JAD-150728

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 33-44, 2016

Authors: Wang, Hua-Long | Wang, Yan-Yong | Liu, Xin-Gang | Kuo, Sheng-Han | Liu, Na | Song, Qiao-Yun | Wang, Ming-Wei

Article Type: Research Article

Abstract: Abnormal cholesterol metabolism is an established feature of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ 42 , total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried …to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ 42 , total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cholesterol, 24-hydroxycholesterol, 27-hydroxycholesterol

DOI: 10.3233/JAD-150734

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 45-55, 2016

Authors: Grande, Giulia | Cucumo, Valentina | Cova, Ilaria | Ghiretti, Roberta | Maggiore, Laura | Lacorte, Eleonora | Galimberti, Daniela | Scarpini, Elio | Clerici, Francesca | Pomati, Simone | Vanacore, Nicola | Mariani, Claudio

Article Type: Research Article

Abstract: The prognostic value of mild cognitive impairment (MCI) is being questioned, with some MCI subjects reverting to normal cognition (NC). The reversion rate varies mostly depending on the study design, the setting, and both MCI and NC definitions. Previous studies have focused on the profile of subjects who revert to NC, but the role of comorbidities has not been entirely investigated. We aimed to evaluate the proportion of MCI subjects who revert to NC in a memory clinic context, focusing on the role of comorbidities. Between 2004 and 2013, 374 MCI subjects were recruited. During a mean time of 32 …± 25.5 months, 21 subjects (5.6%) reverted to NC. Subjects who reverted to NC were younger (p  = 0.0001), more educated (p  = 0.0001), had a better global cognition (p  = 0.0001), as assessed by the Mini-Mental State Examination (MMSE) and suffered from more comorbidities (p  = 0.002), as assessed by Cumulative Illness Rating Scale (CIRS) than those who developed dementia. The Cox Regression Model, constructed to adjust for the confounders, showed that the higher were the MMSE (HR = 1.83, CI 95%: 1.07–3.11) and the CIRS score (HR = 1.3, CI 95% 0.88–1.92) at baseline, the higher was the probability of returning to NC than developing dementia, though the last association was not significant. Subjects who reverted to NC were more frequently affected by respiratory (p  = 0.002), urologic (p  = 0.012), and psychiatric (p  = 0.012) diseases. The cognitive performance of subjects with medical comorbidities could benefit from preventive strategies aimed at treating the underlying diseases. Show more

Keywords: Comorbidity, dementia, mild cognitive impairment, prevention

DOI: 10.3233/JAD-150786

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 57-67, 2016

Authors: Morin, Jean-Pascal | Cerón-Solano, Giovanni | Velázquez-Campos, Giovanna | Pacheco-López, Gustavo | Bermúdez-Rattoni, Federico | Díaz-Cintra, Sofía

Article Type: Research Article

Abstract: Dysfunction of synaptic communication in cortical and hippocampal networks has been suggested as one of the neuropathological hallmarks of the early stages of Alzheimer’s disease (AD). Also, several lines of evidence have linked disrupted levels of activity-regulated cytoskeletal associated protein (Arc), an immediate early gene product that plays a central role in synaptic plasticity, with AD “synaptopathy”. The mapping of Arc expression patterns in brain networks has been extensively used as a marker of memory-relevant neuronal activity history. Here we evaluated basal and behavior-induced Arc expression in hippocampal networks of the 3xTg-AD mouse model of AD. The basal percentage of …Arc-expressing cells in 10-month-old 3xTg-AD mice was higher than wild type in CA3 (4.88% versus 1.77% , respectively) but similar in CA1 (1.75% versus 2.75% ). Noteworthy, this difference was not observed at 3 months of age. Furthermore, although a Morris water maze test probe induced a steep (∼4-fold) increment in the percentage of Arc+ cells in the CA3 region of the 10-month-old wild-type group, no such increment was observed in age-matched 3xTg-AD, whereas the amount of Arc+ cells in CA1 increased in both groups. Further, we detected that CA3 neurons with amyloid-β were much more likely to express Arc protein under basal conditions. We propose that in 3xTg-AD mice, intraneuronal amyloid-β expression in CA3 could increase unspecific neuronal activation and subsequent Arc protein expression, which might impair further memory-stabilizing processes. Show more

Keywords: Activity regulated cytoskeletal-associated protein, Alzheimer’s disease, hippocampus, memory, neuroplasticity

DOI: 10.3233/JAD-150975

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 69-79, 2016

Authors: Manso, Yasmina | Comes, Gemma | López-Ramos, Juan C. | Belfiore, Mónica | Molinero, Amalia | Giralt, Mercedes | Carrasco, Javier | Adlard, Paul A. | Bush, Ashley I. | Delgado-García, José María | Hidalgo, Juan

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most commonly diagnosed dementia, where signs of neuroinflammation and oxidative stress are prominent. In this study we intend to further characterize the roles of the antioxidant, anti-inflammatory, and heavy metal binding protein, metallothionein-1 (MT-1), by crossing Mt1 overexpressing mice with a well-known mouse model of AD, Tg2576 mice, which express the human amyloid-β protein precursor (hAβPP) with the Swedish K670N/M671L mutations. Mt1 overexpression increased overall perinatal survival, but did not affect significantly hAβPP-induced mortality and weight loss in adult mice. Amyloid plaque burden in ∼14-month-old mice was increased by Mt1 overexpression in …the hippocampus but not the cortex. Despite full length hAβPP levels and amyloid plaques being increased by Mt1 overexpression in the hippocampus of both sexes, oligomeric and monomeric forms of Aβ, which may contribute more to toxicity, were decreased in the hippocampus of females and increased in males. Several behavioral traits such as exploration, anxiety, and learning were altered in Tg2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAβPP on exploration in young females, and potentiated those on anxiety in old males, and seemed to improve the rate of spatial learning (Morris water maze) and the learning elicited by a classical conditioning procedure (eye-blink test). These results clearly suggest that MT-1 may be involved in AD pathogenesis. Show more

Keywords: Alzheimer’ disease, amyloid plaques, behavior, body weight, gliosis, metallothionein-1, metals, survival, Tg2576

DOI: 10.3233/JAD-151025

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 81-95, 2016