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

Authors: Weise, David | Tiepolt, Solveig | Awissus, Carolin | Hoffmann, Karl-Titus | Lobsien, Donald | Kaiser, Thorsten | Barthel, Henryk | Sabri, Osama | Gertz, Hermann-Josef

Article Type: Research Article

Abstract: Background: Biomarkers of neuronal injury and amyloid pathology play a pivotal role in the diagnosis of Alzheimer’s disease (AD). The degree of AD biomarker congruence is still unclear in clinical practice. Objective: Diagnosis of AD with regard to the congruence of the clinical diagnosis and different biomarkers. Methods: In this prospective cross-sectional observational study, 54 patients with mild cognitive impairment or dementia due to AD or not due to AD were investigated. Biomarkers of neuronal injury were medial temporal lobe atrophy (MTA) on magnetic resonance imaging (MRI) and tau concentration in the cerebrospinal fluid (CSF). …CSF Aβ1-42 and amyloid-targeting positron emission tomography (PET) were considered as biomarkers of amyloid pathology. Results: Forty cases were diagnosed as AD and 14 cases were diagnosed as non-AD based on clinical and routine MRI assessment. AD cases had higher MTA scores, higher levels of CSF tau and lower levels of CSF Aβ1 - 42, and higher amyloid load on PET compared to the non-AD group. In the AD group, completely consistently pathological biomarkers were found in 32.5% , non-pathological in 5% . In 62.5% the findings were inconsistent. Congruence of biomarkers was 67.5% for neuronal injury and for amyloid dysfunction, respectively. In two patients, clinical diagnosis switched to non-AD due to completely consistent non-pathological biomarker findings. The criteria of the international working group were met in 75.0% . Conclusion: Surprisingly, the number of completely congruent biomarkers was relatively low. Interpretation of AD biomarkers is complicated by multiple biomarker constellations. However, the level of biomarker consistency required to reliably diagnose AD remains uncertain. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, dementia, magnetic resonance imaging, positron emission tomography

DOI: 10.3233/JAD-150229

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 425-432, 2015

Authors: Lewczuk, Piotr | Kornhuber, Johannes | on behalf of the German Dementia Competence Network | Toledo, Jon B. | Trojanowski, John Q. | Knapik-Czajka, Malgorzata | Peters, Oliver | Wiltfang, Jens | Shaw, Leslie M. | on behalf of the US-ADNI

Article Type: Research Article

Abstract: Background: In previous studies, a dichotomous stratification of subjects into “cerebrospinal fluid (CSF) normal” and “CSF pathologic” was used to investigate the role of biomarkers in the prediction of progression to dementia in pre-dementia/mild cognitive impairment subjects. With the previously published Erlangen Score Algorithm, we suggested a division of CSF patterns into five groups, covering all possible CSF result combinations based on the presence of pathologic tau and/or amyloid-β CSF values. Objective: This study aimed to validate the Erlangen Score diagnostic algorithm based on the results of biomarkers analyses obtained in different patients cohorts, with …different pre-analytical protocols, and with different laboratory analytical platforms. Methods: We evaluated the algorithm in two cohorts of pre-dementia subjects: the US-Alzheimer’s Disease Neuroimaging Initiative and the German Dementia Competence Network. Results: In both cohorts, the Erlangen scores were strongly associated with progression to Alzheimer’s disease. Neither the scores of the progressors nor the scores of the non-progressors differed significantly between the two projects, in spite of significant differences in the cohorts, laboratory methods, and the samples treatment. Conclusions: Our findings confirm the utility of the Erlangen Score algorithm as a useful tool in the early neurochemical diagnosis of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, clinical neurochemistry, results interpretation, validation

DOI: 10.3233/JAD-150342

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 433-441, 2015

Authors: Leifert, Wayne R. | Nguyen, Tori | Rembach, Alan | Martins, Ralph | Rainey-Smith, Stephanie | Masters, Colin L. | Ames, David | Rowe, Christopher C. | Macaulay, S. Lance | François, Maxime | Fenech, Michael F. | and the Australian Imaging, Biomarkers and Lifestyle Study Research Group

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) may reflect early stages of neurodegenerative disorders such as Alzheimer’s disease (AD). Our hypothesis was that cytokeratin 14 (CK14) expression could be used with blood-based biomarkers such as homocysteine, vitamin B12, and folate to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Buccal cells from 54 individuals were analyzed by a newly developed method that is rapid, automated, and quantitative for buccal cell CK14 expression levels. CK14 was negatively correlated with plasma Mg2 + and LDL, while positively correlated with vitamin B12, red cell hematocrit/volume, and …basophils in the MCI group and positively correlated with insulin and vitamin B12 in the AD group. The combined biomarker panel (CK14 expression, plasma vitamin B12, and homocysteine) was significantly lower in the MCI (p  = 0.003) and AD (p  = 0.0001) groups compared with controls. Receiver-operating characteristic curves yielded area under the curve (AUC) values of 0.829 for the MCI (p  = 0.002) group and 0.856 for the AD (p  = 0.0003) group. These complex associations of multiple related parameters highlight the differences between the MCI and AD cohorts and possibly an underlying metabolic pathology associated with the development of early memory impairment. The changes in buccal cell CK14 expression observed in this pilot study supports previous results suggesting the peripheral biomarkers and metabolic changes are not restricted to brain pathology alone in MCI and AD and could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD. Show more

Keywords: Alzheimer’s disease, buccal mucosa, cytokeratin, imaging, immunofluorescence, mild cognitive impairment

DOI: 10.3233/JAD-150330

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 443-452, 2015

Authors: Kiosses, Dimitris N. | Rosenberg, Paul B. | McGovern, Amanda | Fonzetti, Pasquale | Zaydens, Hana | Alexopoulos, George S.

Article Type: Research Article

Abstract: Background: Depression is prevalent in dementia and contributes to poor outcomes for patients and their families. Antidepressants have limited efficacy in older adults with major depression and dementia, and psychosocial interventions are under-investigated. Objective: To examine the course, predictors and moderators of depression and suicidal ideation during 12 weeks of home-delivered Problem Adaptation Therapy (PATH) versus Supportive Therapy for Cognitively Impaired Older Adults (ST-CI) in 39 older adults with major depression and dementia. Methods: Thirty-nine older adults with major depression, mild or moderate dementia, and disability participated in a randomized controlled trial …that compared the efficacy of PATH versus ST-CI. Depression and suicidal ideation were assessed with Cornell Scale for Depression in Dementia Total Score and Suicide Item. Results: PATH participants had significantly greater reduction in depression than ST-CI participants over 12 weeks of treatment. PATH participants with high social support had the greatest reduction in depression. Both treatments had comparable reduction in suicidal ideation. Conclusion: PATH is more effective in reducing depression in older adults with major depression and dementia compared to ST-CI. These results are clinically significant as antidepressants have limited efficacy in this population. Home-delivered psychosocial treatments may reduce suicidal ideation in this population. Show more

Keywords: Dementia, depression, psychosocial interventions, social support, suicidal ideation

DOI: 10.3233/JAD-150200

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 453-462, 2015

Authors: Liao, Xiang | Li, Guangming | Wang, Anguo | Liu, Tao | Feng, Shenggang | Guo, Zhiwei | Tang, Qing | Jin, Yu | Xing, Guoqiang | McClure, Morgan A. | Chen, Huaping | He, Bin | Liu, Hua | Mu, Qiwen

Article Type: Research Article

Abstract: Background: Recent studies have indicated that repetitive transcranial magnetic stimulation (rTMS) could improve cognitive function in people with Alzheimer’s disease (AD). Yet the results are inconclusive. Objective: This meta-analysis aimed to evaluate recent rTMS studies conducted in mild to moderate AD patients. Methods: PubMed, Embase, MEDLINE databases and Science Direct were searched for studies of rTMS treatment on AD patients with cognitive impairment published before February 2015. The relevant primary outcomes of cognition were extracted from those included studies. A crude standardized mean difference (SMD) with 95% confidence interval (CI) was calculated …by using random effect models. Results: Seven studies with a total of 94 mild to moderate AD patients were included in this meta-analysis. A significant overall rTMS treatment effect on cognition was found for all AD patients (p  = 0.0008, SMD = 1.00, 95% CI = 0.41–1.58). Stratification analysis showed that this effect is stimulation frequency- and hemisphere-dependent. High frequency stimulation (>1.0 Hz) (p  <  0.05) but not low frequency stimulation (≤1.0 Hz) (p  >  0.05) was significantly effective in improving the cognition of AD patients. Further, rTMS stimulation on right dorsolateral prefrontal cortex (DLPFC) and bilateral DLPFC (p  <  0.05), but not on the left DLPFC (p  >  0.05) was significantly effective in improving cognitive function of AD patients. A significant effect was observed in the rTMS subgroup (p  <  0.05), rather than in the rTMS+drug subgroup (p  >  0.05). Conclusion: This meta-analysis supports that high frequency rTMS stimulation on right- or bilateral-DLPFC has significant therapeutic effect on cognitive function in patients with mild to moderate AD. Due to small number of studies included, more well-controlled rTMS studies should be evaluated in AD patients in the future. Show more

Keywords: Alzheimer’s disease, meta-analysis, mild to moderate cognitive impairment, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-150346

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 463-472, 2015

Authors: Gauthier, Serge | Rountree, Susan | Finn, Barbara | LaPlante, Barbra | Weber, Eckard | Oltersdorf, Tilman

Article Type: Research Article

Abstract: Background and Objective: ST101, an acetylcholine release agent with efficacy in rodent memory and cognition models, was assessed for clinical safety and efficacy. Methods: A phase 2 double blind, placebo-controlled study enrolled 210 AD patients (MMSE 10–20) on 10 mg donepezil QD. Patients received ST101 (10, 60, or 120 mg QD) or placebo for 12 weeks. The primary endpoint was change in cognitive function measured by ADAS-cog in the modified Intent To Treat (MITT) population and the Per Protocol (PP) population. Results: Mean ADAS-cog change favored ST101 over placebo in the MITT population (p … = 0.0957, one-sided) and in the PP population (p  = 0.0434, one-sided, ∼1.5 point drug-placebo difference) comparing all ST101 dose groups combined to placebo. Among secondary and exploratory outcome measures the ADCS-CGIC also showed a beneficial trend (p  = 0.0294, one-sided). In a post-hoc analysis, the subgroup with more severe disease (MMSE 10–17) showed a dose response in the ADAS-cog with the greatest efficacy at 120 mg (p  = 0.0067, one sided). No significant ST101-related safety concerns were identified. Conclusion: The study supports the possibility that ST101, in patients receiving a stable dose of donepezil, may provide additional symptomatic benefit in moderate AD. Show more

Keywords: Alzheimer’s disease, cholinergic agents, clinical trial, Phase II, donepezil

DOI: 10.3233/JAD-150414

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 473-481, 2015

Authors: Leoutsakos, Jeannie-Marie S. | Forrester, Sarah N. | Lyketsos, Constantine.G. | Smith, Gwenn S.

Article Type: Research Article

Abstract: Background: A number of studies have linked neuropsychiatric symptoms to increase risk of dementia. Objective: To determine if risk of conversion to mild cognitive impairment or dementia among healthy controls varied as a function of their pattern of neuropsychiatric symptoms. Method: We studied individuals in the National Alzheimer Coordinating Center dataset collected from 34 Alzheimer Disease Centers between 2005 and 2013. The analysis included 4,517 volunteers who were ≥60 years old, cognitively normal, and had complete Neuropsychiatric Inventory data at their baseline visit, and had at least one follow-up. We used latent …class analysis to identify four classes based on patterns of NPI symptoms. We used a Cox proportional hazards model to determine if time to MCI or dementia varied by baseline latent class membership. Results: We identified four latent classes of neuropsychiatric symptoms: irritable, depressed, complex (depression, apathy, irritability, and nighttime behaviors) and asymptomatic. 873 participants converted to MCI or dementia. Hazard ratios for conversion by class were 1.76 (95% CI: 1.34, 2.33) for the irritable class, 3.20 (95% CI: 2.24, 4.58) for the complex class, and 1.90 (95% CI: 1.49, 2.43) for the depressed class, with the asymptomatic class as the reference. Conclusions: Membership in all three symptomatic classes was associated with greater risk of conversion to MCI or dementia; the complex class had the greatest risk. Different patterns of neuropsychiatric symptoms may represent different underlying neuropathological pathways to dementia. Further work imaging and pathology research is necessary to determine if this is the case. Show more

Keywords: Alzheimer’s disease, dementia, depression, latent class analysis, neuropsychiatric symptoms

DOI: 10.3233/JAD-150421

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 483-493, 2015

Authors: Sarlus, Heela | Eyjolfsdottir, Helga | Eriksdotter, Maria | Oprica, Mircea | Schultzberg, Marianne

Article Type: Research Article

Abstract: Background: Peripheral inflammation has been suggested to influence the development of Alzheimer’s disease (AD). Elevated levels of pro-inflammatory markers in the plasma of patients with AD indicate that a systemic pro-inflammatory status occurs concomitantly with inflammatory changes in the brain. Objective: To investigate whether allergy influences the levels of immunoglobulins (Ig) and of pro- and anti-inflammatory cytokines in the serum and cerebrospinal fluid (CSF) from patients with AD, mild cognitive impairment (MCI), and subjective cognitive impairment (SCI). Methods: IgA, IgG, and its subclasses, IgM, and cytokines were analyzed in CSF and serum …from patients with SCI, MCI, and AD, with or without allergy. The relation between allergy and Mini-Mental State Examination (MMSE) scores, and between allergy and CSF biomarkers for AD (phosphorylated (p)-tau, total (t)-tau, amyloid-β 42 (Aβ42 ), were analyzed. Results: In MCI, the CSF levels of IgG2 were lower in allergic patients, and in AD, the levels of IgA and the IgG1/total IgG ratio were lower in allergic patients, compared to patients without allergy. MCI subjects with allergy had higher serum IgM levels compared to those without allergy. CSF levels of Aβ42 were lower and MMSE scores were higher in AD patients with allergy than in those without allergy. Conclusions: The presence of allergy was associated with seemingly beneficial effects on AD as suggested by higher Aβ42 levels in CSF, and higher MMSE scores. Higher IgM levels and lower other Ig classes suggest that allergy may influence senescence of the immune response. Show more

Keywords: Cerebrospinal fluid, cytokines, mild cognitive impairment, Mini-Mental State Examination, serum, subjective cognitive impairment, systemic inflammation, tau

DOI: 10.3233/JAD-143147

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 495-505, 2015

Authors: Sarajärvi, Timo | Marttinen, Mikael | Natunen, Teemu | Kauppinen, Tarja | Mäkinen, Petra | Helisalmi, Seppo | Laitinen, Marjo | Rauramaa, Tuomas | Leinonen, Ville | Petäjä-Repo, Ulla | Soininen, Hilkka | Haapasalo, Annakaisa | Hiltunen, Mikko

Article Type: Research Article

Abstract: The agonist-induced activation of human δ -opioid receptor (δ OR) has been shown to increase β- (BACE1) and γ -secretase activities leading to increased production of amyloid-β (Aβ) peptide. We have recently shown that phenylalanine to cysteine substitution at amino acid 27 in δ OR (δ OR-Phe27Cys) increases amyloid-β protein precursor processing through altered endocytic trafficking. Also, a genetic meta-analysis of the δ OR-Phe27Cys variation (rs1042114) in two independent Alzheimer’s disease (AD) patient cohorts indicated that the heterozygosity of δ OR-Phe27Cys increases the risk of AD. Here, we investigated α -, β-, and γ -secretase activities in human brain with …respect to δ OR-Phe27Cys variation in the temporal cortex of 71 subjects with varying degree of AD-related neurofibrillary pathology (Braak stages I-VI). As a result, a significant increase in β- (p  = 0.03) and γ - (p  = 0.01), but not α -secretase, activities was observed in late stage AD samples (Braak stages V-VI), which were heterozygous for δ OR-Phe27Cys as compared to the δ OR-Phe27 and δ OR-Cys27 homozygotes. The augmented β-secretase activity was not associated with increased mRNA expression or protein levels of BACE1 in the late stage AD patients, who were heterozygous for the δ OR-Phe27Cys variation. These findings suggest that δ OR-Phe27Cys variation modulates β- and γ -secretase activity in the late stages of AD likely via post-translational mechanisms other than alterations in the mRNA or protein levels of BACE1, or, in the expression of γ -secretase complex components. Show more

Keywords: Alzheimer disease, amyloid-β, amyloid-β protein precursor, β-secretase, γ-secretase, δ-opioid receptor

DOI: 10.3233/JAD-150221

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 507-516, 2015

Authors: Samuraki, Miharu | Matsunari, Ichiro | Yoshita, Mitsuhiro | Shima, Keisuke | Noguchi-Shinohara, Moeko | Hamaguchi, Tsuyoshi | Ono, Kenjiro | Yamada, Masahito

Article Type: Research Article

Abstract: Background: Microbleeds (MBs) are frequently observed in Alzheimer’s disease (AD); however, the relevance to AD pathophysiology has not been elucidated. Objectives: We investigated correlation of MBs, especially cerebral amyloid angiopathy (CAA)-related MBs with cognitive function, gray matter volume, and glucose metabolism in AD. Methods: We performed magnetic resonance imaging including T2* -weighted imaging sequence for 206 patients with AD. Among them, 158 AD patients with no focal brain lesions except for MBs were investigated with cognitive tests, voxel-based morphometry, and 18 F-fluorodeoxyglucose positron emission tomography in a cross-sectional observational study. …Results: Of the 158 patients with no hemorrhagic and/or ischemic stroke lesions except for MBs, 27 patients had MBs, in which 17 patients showed CAA-related MBs that located only in cortex/subcortex (CAA-related MBs), and 10 patients showed CAA-unrelated MBs that located in deep regions regardless of the presence of MBs in cortical/subcortical regions. There were slightly but significant differences in cognitive functions between the patients without MBs, those with CAA-related MBs, and those with CAA-unrelated MBs. MBs were recognized frequently in the occipital lobe in the patients with CAA-related MBs. The patients with CAA-related MBs showed gray matter atrophy in the temporal lobe and cerebellum, and glucose hypometabolism in the temporal lobe compared with those without MBs. Conclusions: Our results indicate that MBs, particularly CAA-related MBs would cause gray matter atrophy and glucose hypometabolism in AD. Show more

Keywords: Alzheimer’s disease, brain microbleeds, cerebral amyloid angiopathy, 18F-FDG PET, voxel-based morphometry

DOI: 10.3233/JAD-150274

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 517-528, 2015

Authors: El Haj, Mohamad | Gély-Nargeot, Marie-Christine | Raffard, Stéphane

Article Type: Research Article

Abstract: Destination memory, or the ability to remember the destination to whom a piece of information was addressed, is found to be compromised in Alzheimer’s disease (AD). Our paper investigated the relationship between destination memory and theory of mind in AD since both destination memory and theory of mind are social abilities that require processing attributes of interlocutors. Mild AD participants and controls were administered tasks tapping destination memory, affective theory of mind, and 1st and 2nd order cognitive theory of mind. Relative to controls, AD participants showed compromise in destination memory and 2nd order cognitive theory of mind, but preserved …performance on affective and 1st order cognitive theory of mind. Significant correlations were observed between destination memory, and 1st and 2nd order cognitive theory of mind in AD participants and controls. By demonstrating a relationship between compromises in 2nd order theory of mind and in destination memory, our work highlights links between social cognition and memory functioning in AD. Show more

Keywords: Alzheimer’s disease, destination memory, episodic memory, social cognition, theory of mind

DOI: 10.3233/JAD-150467

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 529-536, 2015

Authors: Wood, Paul L. | Medicherla, Srikanth | Sheikh, Naveen | Terry, Bradley | Phillipps, Aaron | Kaye, Jeffrey A. | Quinn, Joseph F. | Woltjer, Randall L.

Article Type: Research Article

Abstract: Previous studies have demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of Alzheimer’s disease (AD) patients. We extended these findings from non-targeted lipidomics studies to design a lipidomics platform to interrogate DAGs and monoacylglycerols (MAG) in the frontal cortex and plasma of MCI subjects. Control subjects included both aged normal controls and controls with normal cognition, but AD pathology at autopsy, individuals termed non-demented AD neuropathology. DAGs with saturated, unsaturated, and polyunsaturated fatty acid substituents were found to be elevated in MCI frontal cortex and plasma. Tandem mass spectrometry of the DAGs did not reveal any …differences in the distributions of the fatty acid substitutions between MCI and control subjects. While triacylglycerols were not altered in MCI subjects there were increases in MAG levels both in the frontal cortex and plasma. In toto , increased levels of DAGs and MAGs appear to occur early in AD pathophysiology and require both further validation in a larger patient cohort and elucidation of the lipidomics alteration(s) that lead to the accumulation of DAGs in MCI subjects. Show more

Keywords: Alzheimer’s disease, diacylglycerols, mild cognitive impairment, monoacylglycerols

DOI: 10.3233/JAD-150336

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 537-546, 2015

Authors: Reddy, P. Hemachandra | Blackmon, Joan | Molinar-Lopez, Veronica | Ament, Clay | Manczak, Maria | Kandimalla, Ramesh | Yin, Xianglin | Pandey, Akhilesh | Kuruva, Chandra Sekhar | Wang, Rui | Fry, David | Osborn, Carrah | Stonum, Kathleen | Quesada, Kandi | Gonzales, Ruben | Boles, Annette

Article Type: Research Article

Abstract: The Garrison Institute on Aging (GIA) is an established institute within Texas Tech University Health Sciences Center, whose mission is to promote healthy aging through cutting-edge research on Alzheimer’s disease (AD) and other diseases of aging through innovative educational opportunities for students, clinicians, researchers, health care professionals, and the public. The GIA has multiple programs, including both research and education on healthy aging and AD, community outreach, caregiving, the Retired Senior Volunteer Program, Healthy Lubbock, the GIA Brain Bank, healthy aging seminars, research seminars, and collaborations and scholarships. The GIA programs connect basic and clinical researchers and health care professionals, …and provide a unique environment to help our growing elderly population and patients with AD and their families. Show more

DOI: 10.3233/JAD-150490

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 547-555, 2015

Article Type: Meeting Report

DOI: 10.3233/JAD-150604

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 557-561, 2015