Journal of Alzheimer's Disease - Volume 48, issue 2

Authors: Fiala, Milan | Terrando, Niccolo | Dalli, Jesmond

Article Type: Review Article

Abstract: In this review we discuss the immunopathology of Alzheimer’s disease (AD) and recent advances in the prevention of minor cognitive impairment (MCI) by nutritional supplementation with omega-3 fatty acids. Defective phagocytosis of amyloid-β (Aβ) and abnormal inflammatory activation of peripheral blood mononuclear cells (PBMCs) are the two key immune pathologies of MCI and AD patients. The phagocytosis of Aβ by PBMCs of MCI and AD patients is universally defective and the inflammatory gene transcription is heterogeneously deregulated in comparison to normal subjects. Recent studies have discovered a cornucopia of beneficial anti-inflammatory and pro-resolving effects of the specialized proresolving mediators (SPMs) …resolvins, protectins, maresins, and their metabolic precursors. Resolvin D1 and other mediators switch macrophages from an inflammatory to a tissue protective/pro-resolving phenotype and increase phagocytosis of Aβ. In a recent study of AD and MCI patients, nutritional supplementation by omega-3 fatty acids individually increased resolvin D1, improved Aβ phagocytosis, and regulated inflammatory genes toward a physiological state, but only in MCI patients. Our studies are beginning to dissect positive factors (adherence to Mediterranean diet with omega-3 and exercise) and negative factors (high fat diet, infections, cancer, and surgeries) in each patient. The in vitro and in vivo effects of omega-3 fatty acids and SPMs suggest that defective phagocytosis and chronic inflammation are related to defective production and/or defective signaling by SPMs in immune cells. Show more

Keywords: Amyloid-β, fatty acids, inflammation, mild cognitive impairment, omega-3

DOI: 10.3233/JAD-150367

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 293-301, 2015

Authors: Pistollato, Francesca | Cano, Sandra Sumalla | Elio, Iñaki | Vergara, Manuel Masias | Giampieri, Francesca | Battino, Maurizio

Article Type: Review Article

Abstract: In the last decade, specific dietary patterns, mainly characterized by high consumption of vegetables and fruits, have been proven beneficial for the prevention of both metabolic syndrome (MetS)-related dysfunctions and neurodegenerative disorders, such as Alzheimer’s disease (AD). Nowadays, neuroimaging readouts can be used to diagnose AD, investigate MetS effects on brain functionality and anatomy, and assess the effects of dietary supplementations and nutritional patterns in relation to neurodegeneration and AD-related features. Here we review scientific literature describing the use of the most recent neuroimaging techniques to detect AD- and MetS-related brain features, and also to investigate associations between consolidated dietary …patterns or nutritional interventions and AD, specifically focusing on observational and intervention studies in humans. Show more

Keywords: Alzheimer’s disease, brain anatomy, imaging, magnetic resonance imaging, metabolic syndrome, mild cognitive impairment, nutrient supplementations, nutritional patterns, positron emission tomography, type 2 diabetes

DOI: 10.3233/JAD-150301

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 303-318, 2015

Authors: Harris, Steven A. | Harris, Elizabeth A.

Article Type: Review Article

Abstract: This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflammatory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae , Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and …bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid-β (Aβ) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae , and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori , and periodontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of Aβ damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae . ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials. Show more

Keywords: Alzheimer’s disease, ApoE4, amyloid, Cytomegalovirus, dementia, Herpes simplex, neurodegeneration, pathogen

DOI: 10.3233/JAD-142853

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 319-353, 2015

Authors: Alexander, Myriam | Perera, Gayan | Ford, Lisa | Arrighi, H. Michael | Foskett, Nadia | Debove, Catherine | Novak, Gerald | Gordon, Mark Forrest

Article Type: Short Communication

Abstract: The prevalence of mild cognitive impairment (MCI) and dementia according to age remain uncertain. We systematically extracted age-stratified estimates of MCI and dementia prevalence reported in European studies published since 1995, and performed meta-analyses for dementia. We identified 10 relevant studies on MCI and 26 studies on dementia. Studies on MCI presented substantial heterogeneity preventing a meta-analysis, with a majority reporting an increase in prevalence at ≥75 years old. Pooled prevalence of dementia rose continuously from 55 years of age, reaching 44.7% (39.8; 49.6) in those ≥95 years of age. Homogenization of MCI criteria, and additional studies in Northern European …population would be warranted. Show more

Keywords: Dementia, epidemiology, mild cognitive impairment, prevalence

DOI: 10.3233/JAD-150168

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 355-359, 2015

Authors: Beydoun, May A. | Beydoun, Hind A. | Gamaldo, Alyssa A. | Rostant, Ola S. | Dore, Greg A. | Zonderman, Alan B. | Eid, Shaker M.

Article Type: Research Article

Abstract: In the inpatient setting, prevalence, predictors, and outcomes [mortality risk (MR), length of stay (LOS), and total charges (TC)] of Alzheimer’s disease (AD) are largely unknown. We used data on older adults (60+ y) from the Nationwide Inpatient Sample (NIS) 2002–2012. AD prevalence was ∼3.12% in 2012 (total weighted discharges with AD ± standard error: 474, 410 ± 6,276). Co-morbidities prevailing more in AD inpatient admissions included depression (OR = 1.67, 95% CI: 1.63–1.71, p  <  0.001), fluid/electrolyte disorders (OR = 1.25, 95% CI: 1.22–1.27, p  <  0.001), weight loss (OR = 1.26, 95% CI: 1.22–1.30, p  <  0.001), and psychosis (OR = 2.59, 95% CI: 2.47–2.71, p … <  0.001), with mean total co-morbidities increasing over time. AD was linked to higher MR and longer LOS, but lower TC. TC rose in AD, while MR and LOS dropped markedly over time. In AD, co-morbidities predicting simultaneously higher MR, TC, and LOS (2012) included congestive heart failure, chronic pulmonary disease, coagulopathy, fluid/electrolyte disorders, metastatic cancer, paralysis, pulmonary circulatory disorders, and weight loss. In sum, co-morbidities and TC increased over time in AD, while MR and LOS dropped. Few co-morbidities predicted occurrence of AD or adverse outcomes in AD. Show more

Keywords: Alzheimer’s disease, co-morbidity, health care cost, inpatient sample, length of stay, mortality, older adults

DOI: 10.3233/JAD-150228

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 361-375, 2015

Authors: Rea, Raffaele | Carotenuto, Anna | Traini, Enea | Fasanaro, Angiola Maria | Manzo, Valentino | Amenta, Francesco

Article Type: Research Article

Abstract: Background: Apathy is a common symptom in Alzheimer’s disease (AD), but no treatment has proven to be effective, although administration of cholinesterase inhibitors has been associated with moderate improvements in the short term. Objective: This study has compared apathy scores of patients included in “ASCOMALVA” trial treated for two years with donepezil plus a cholinergic precursor (choline alphoscerate), to those of patients receiving donepezil alone with the purpose of assessing if the availability of a higher amount of acetylcholine by combining precursor loading and inhibition of neurotransmitter breakdown would counter apathy in AD. …Methods: Apathy was measured at baseline and 3, 6, 9, 12, 18, and 24 months using the apathy subtest of the Neuropsychiatric Inventory in 113 mild-moderate AD patients. Two matched groups were compared: group 1 (56 subjects) treated with donepezil plus choline alphoscerate and group 2 (57 subjects) treated with donepezil alone. Frontal functions were explored by the Frontal Assessment Battery (FAB) at baseline. Results: Group 1 subjects showed, as a whole, a lower apathy score after 12 to 24 months. The caregiver distress was descreased after 6 to 24 months. Results were unrelated with cognitive scores measured by the MMSE and ADAS-cog test. Subjects with FAB in the normal range had significantly lower scores. Conclusions: The combination of donepezil with choline alphoscerate is more effective than donepezil alone in countering symptoms of apathy in AD. This suggests that the availability in brain of a higher amount of acetylcholine could affect apathy in AD subjects with spared executive functions. Show more

Keywords: Alzheimer’s disease, apathy, choline alphoscerate, donepezil, executive functions

DOI: 10.3233/JAD-141983

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 377-383, 2015

Authors: Chopard, Gilles | Puyraveau, Marc | Binetruy, Mickael | Meyer, Agatha | Vandel, Pierre | Magnin, Eloi | Berger, Eric | Galmiche, Jean | Mauny, Frédéric

Article Type: Research Article

Abstract: Background: A single cutoff is widely used to screen amnestic mild cognitive impairment (aMCI). However, results of screening test performance are never adjusted for spectrum effect and spectrum bias. Objectives: To assess the potential impact of spectrum effect and spectrum bias on screening test performance and clinical decision. Methods: The ability of the combination of Memory Impairment Screen (MIS), the Isaacs Set Test (IST), and the Mini-Mental State Examination (MMSE) to distinguish aMCI (n  = 3,330) from patients with subjective cognitive complaints (SCC) (n  = 1,522) was investigated across a wide range of age …and educational backgrounds. The spectrum effect was defined as the variation of the sensitivity and/or the specificity across different subgroups. A spectrum bias was highlighted if the likelihood ratio (LR) observed in a subgroup of subjects statistically differed from the LR observed in the overall sample. Results: For the MIS-IST pairing, the overall sensitivity and specificity were equal to 72.5% and 75.2% , the positive LR (LR+) and the negative LR (LR–) were equal to 2.91 and 0.37, respectively. Across the different age-education subgroups, the sensitivities ranged from 43.7% to 92.5% and specificities from 39.3% to 95.2%. LR+ and LR– ranged from 1.51 to 9.10 and 0.13 to 0.59, respectively. A statistically significant spectrum bias was found in some subgroups and may result in differences between the post-test probabilities. Similar results were also found for the MMSE. Conclusion: These findings could potentially affect the clinician’s decision with a possible greater impact in elderly patients with a lower educational level. Show more

Keywords: Amnestic mild cognitive impairment, screening, single cutoff, spectrum bias, spectrum effect

DOI: 10.3233/JAD-150195

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 385-393, 2015

Authors: Servello, Adriana | Fioretti, Alessandra | Gualdi, Gianfranco | Di Biasi, Claudio | Pittalis, Angelo | Sollaku, Saadi | Pavaci, Silva | Tortorella, Federica | Fusetti, Marco | Valenti, Marco | Masedu, Francesco | Cacciafesta, Mauro | Marigliano, Vincenzo | Ettorre, Evaristo | Pagliarella, Martina

Article Type: Research Article

Abstract: Background: Olfactory dysfunction is present since the earliest stage of Alzheimer’s disease (AD). In AD patients, the olfactory impairment has been correlated with atrophy of some structures of the olfactory system, but the role of the olfactory bulb remains unclear. Objective: The aim of our work is to test if patients suffering from AD exhibit a statistically significant reduction of the average volume of the olfactory bulb (OBV) compared to healthy subjects. Methods: 78 subjects were enrolled in the study and divided into three groups: 28 healthy elderly (22 females, 6 males, …mean age 69.4 ± 9.2), 25 patients with mild cognitive impairment (MCI) amnestic type (14 females, 11 males, mean age 74.5 ± 7.5), and 25 mild AD patients (14 females, 11 males, mean age 73.7 ± 6.8). Every subject underwent an MRI study of the olfactory bulb and an olfactory assessment with the Sniffin’ Stick Extended Test. Results: The statistical analysis showed no correlation between the OBV and MCI or AD. Moreover, olfactory function and OBV were not correlated in any of the three groups. Conclusion: The reduction of OBV does not seem to represent an index of neuronal damage in the earliest stages of AD. Show more

Keywords: Alzheimer’s disease, hyposmia, mild cognitive impairment, olfactory bulb volume

DOI: 10.3233/JAD-150232

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 395-402, 2015

Authors: Matsunaga, Shinji | Kishi, Taro | Annas, Peter | Basun, Hans | Hampel, Harald | Iwata, Nakao

Article Type: Research Article

Abstract: Background: This is the first meta-analysis of randomized placebo-controlled trials testing lithium as a treatment for patients with Alzheimer’s disease (AD) and individuals with mild cognitive impairment (MCI). Methods: The primary outcome measure was efficacy on cognitive performance as measured through the Alzheimer’s Disease Assessment Scale cognitive subscale or the Mini-Mental State Examination. Other outcome measures were drug discontinuation rate, individual side effects, and biological markers (phosphorylated tau 181, total tau, and amyloid-β42 ) in cerebrospinal fluid (CSF). Results: Three clinical trials including 232 participants that met the study’s inclusion criteria were …identified. Lithium significantly decreased cognitive decline as compared to placebo (standardized mean difference = –0.41, 95% confidence interval = –0.81 to –0.02, p  = 0.04, I 2  = 47% , 3 studies, n  = 199). There were no significant differences in the rate of attrition, discontinuation due to all causes or adverse events, or CSF biomarkers between treatment groups. Conclusions: The results indicate that lithium treatment may have beneficial effects on cognitive performance in subjects with MCI and AD dementia. Show more

Keywords: Alzheimer’s disease, lithium, meta-analysis, mild cognitive impairment, systematic review

DOI: 10.3233/JAD-150437

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 403-410, 2015

Authors: Keeney, Jeriel Thomas-Richard | Ibrahimi, Shaher | Zhao, Liqin

Article Type: Research Article

Abstract: Three major genetic isoforms of apolipoprotein E (ApoE ), ApoE2 , ApoE3 , and ApoE4 , exist in humans and lead to differences in susceptibility to Alzheimer’s disease (AD). This study investigated the impact of human ApoE isoforms on brain metabolic pathways involved in glucose utilization and amyloid-β (Aβ) degradation, two major areas that are significantly perturbed in preclinical AD. Hippocampal RNA samples from middle-aged female mice with targeted human ApoE2 , ApoE3 , and ApoE4 gene replacement were comparatively analyzed with a qRT-PCR custom array for the expression of 85 genes involved in insulin/insulin-like growth factor (Igf) signaling. …Consistent with its protective role against AD, ApoE2 brain exhibited the most metabolically robust profile among the three ApoE genotypes. When compared to ApoE2 brain, both ApoE3 and ApoE4 brains exhibited markedly reduced levels of Igf1, insulin receptor substrates (Irs), and facilitated glucose transporter 4 (Glut4), indicating reduced glucose uptake. Additionally, ApoE4 brain exhibited significantly decreased Pparg and insulin-degrading enzyme (Ide), indicating further compromised glucose metabolism and Aβ dysregulation associated with ApoE4. Protein analysis showed significantly decreased Igf1, Irs, and Glut4 in ApoE3 brain, and Igf1, Irs, Glut4, Pparg, and Ide in ApoE4 brain compared to ApoE2 brain. These data provide the first documented evidence that human ApoE isoforms differentially affect brain insulin/Igf signaling and downstream glucose and amyloid metabolic pathways, illustrating a potential mechanism for their differential risk in AD. A therapeutic strategy that enhances brain insulin/Igf1 signaling activity to a more robust ApoE2-like phenotype favoring both energy production and amyloid homeostasis holds promise for AD prevention and early intervention. Show more

Keywords: Alzheimer’s disease, apolipoprotein E2, apolipoprotein E3, apolipoprotein E4, early intervention, glucose metabolism, glucose transporter 4, insulin-degrading enzyme, insulin-like growth factor 1, peroxisome proliferator-activated receptor gamma

DOI: 10.3233/JAD-150348

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 411-424, 2015