Journal of Alzheimer's Disease - Volume 38, issue 3

Authors: van Wijk, Nick | Broersen, Laus M. | de Wilde, Martijn C. | Hageman, Robert J.J. | Groenendijk, Martine | Sijben, John W.C. | Kamphuis, Patrick J.G.H.

Article Type: Review Article

Abstract: Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, …phospholipids, folic acid, vitamins B12 , B6 , C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models. Show more

Keywords: Alzheimer's disease, amyloid-β, Fortasyn Connect, membrane, neurotransmission, nutrition, phospholipid, Souvenaid, synaptic dysfunction

DOI: 10.3233/JAD-130998

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 459-479, 2014

Authors: Gainotti, Guido | Quaranta, Davide | Vita, Maria Gabriella | Marra, Camillo

Article Type: Review Article

Abstract: The construct of mild cognitive impairment (MCI) has been proposed to identify patients at risk of developing Alzheimer's disease (AD) in the pre-clinical stage. Although subjects with MCI have an increased risk of progressing to dementia, most remain stable or return to normality. The new criteria for diagnosing prodromal AD assume that, to increase the predictive value of the MCI, in addition to a defect of delayed recall there must also be the presence of abnormal biomarkers, investigating structural and molecular neuroimaging and cerebrospinal fluid (CSF) analysis of amyloid-β or tau proteins. Although acknowledging that the use of CSF degeneration …biomarkers is advisable not only for research, but also for clinical purposes, the present review is centered upon the neuropsychological markers of conversion to AD, which are equally clinically important. In particular, results of this review suggest the following: (a) measures of delayed recall are the best neuropsychological predictors of conversion from MCI to AD; (b) memory tests providing controlled encoding and cued recall are not necessarily better predictors than free recall tests; (c) stringent cut-off points are necessary to increase the specificity of these predictors; (d) multi-domain amnestic MCI patients are the best candidates for clinical trials, but not for treatment with disease-modifying drugs; and (e) not only episodic but also semantic memory is significantly impaired in patients who will convert to AD. These data and the underlying neural mechanisms will be discussed, trying to distinguish results obtained in MCI patients from those obtained in a pre-MCI stage of the AD progression. Show more

Keywords: Delayed recall, episodic memory, mild cognitive impairment, neuropsychology, semantic memory

DOI: 10.3233/JAD-130881

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 481-495, 2014

Authors: Hu, Nan | Tan, Meng-Shan | Yu, Jin-Tai | Sun, Lei | Tan, Lin | Wang, Ying-Li | Jiang, Teng | Tan, Lan

Article Type: Short Communication

Abstract: TREM2 has been reported to be associated with Alzheimer's disease (AD). Here, we evaluated TREM2 mRNA and protein expressions in peripheral blood from AD patients and healthy controls. Higher levels of TREM2 mRNA (p = 0.002) and protein (p < 0.001) were identified in AD patients. We observed a significant correlation between TREM2 expressions and MMSE score (mRNA: r = −0.482, protein: r = −0.582; p < 0.01). According to ROC curve analysis, the diagnostic accuracy for TREM2 protein levels on monocytes was 70%, with the sensitivity and specificity 68% and 72%, respectively. Our results indicate that TREM2 might serve …as a novel noninvasive biomarker for AD diagnosis. Show more

Keywords: Alzheimer's disease, biomarker, blood, diagnosis, mRNA, plasma, protein, TREM2

DOI: 10.3233/JAD-130854

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 497-501, 2014

Authors: Joshi, Yash B. | Di Meco, Antonio | Praticó, Domenico

Article Type: Short Communication

Abstract: Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) pathogenesis, and among them, the pro-inflammatory 5-lipoxygenase (5LO) enzyme. While previous work has shown that 5LO modulates the amyloidotic phenotype of AD, the exact metabolic product responsible for this biological action remains unknown. In this study, we challenged neuronal cells with leukotriene B4 (LTB4 ), a major 5LO product, and found that it increased amyloid-β formation whereby elevating the steady-state levels of the γ-secretase proteins, suggesting that LTB4 is the mediator of the 5LO effect. Therapies that by blocking 5LO activation suppress the formation of LTB4 or its action …represent novel AD therapeutic opportunities. Show more

Keywords: Alzheimer's disease, amyloid-β, γ-secretase, leukotriene B4, 5-lipoxygenase

DOI: 10.3233/JAD-131223

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 503-506, 2014

Authors: Grill, Joshua D. | Zhou, Yan | Karlawish, Jason | Elashoff, David

Article Type: Research Article

Abstract: Most patients with Alzheimer's disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse versus adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer's Coordinating Center Uniform Data Set to examine disease progression in …participants age 55–90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal. Show more

Keywords: Adult children, Alzheimer's disease, caregivers, clinical trial, disease progression, spouses

DOI: 10.3233/JAD-131052

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 507-514, 2014

Authors: Kiddle, Steven J. | Sattlecker, Martina | Proitsi, Petroula | Simmons, Andrew | Westman, Eric | Bazenet, Chantal | Nelson, Sally K. | Williams, Stephen | Hodges, Angela | Johnston, Caroline | Soininen, Hilkka | Kłoszewska, Iwona | Mecocci, Patrizia | Tsolaki, Magda | Vellas, Bruno | Newhouse, Stephen | Lovestone, Simon | Dobson, Richard J. B.

Article Type: Research Article

Abstract: A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes …in five independent research cohorts in these 21 studies: α-1-antitrypsin, α-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency. Show more

Keywords: Alzheimer's disease, biomarkers, blood, magnetic resonance imaging, nucleotide aptamers, proteome

DOI: 10.3233/JAD-130380

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 515-531, 2014

Authors: Ghidoni, Roberta | Flocco, Rosa | Paterlini, Anna | Glionna, Michela | Caruana, Loredana | Tonoli, Elisa | Binetti, Giuliano | Benussi, Luisa

Article Type: Research Article

Abstract: The discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases leading to dementia has brought renewed interest in progranulin and its functions in the central nervous system. Full length progranulin is preserved from cleavage by secretory leukocyte protease inhibitor (SLPI), one of the smallest serine protease inhibitor circulating in plasma. Herein, we investigated the relationship between circulating SLPI and progranulin in affected and unaffected subjects belonging to 26 Italian pedigrees carrying GRN null mutations. In GRN null mutation carriers, we demonstrated: i) an increase of circulating SLPI levels in affected …subjects; ii) an age-related upregulation of the serine-protease inhibitor in response to lifetime progranulin shortage; and iii) a delay in the age of onset in subjects with the highest SLPI protein levels. The study of SLPI and its relation to progranulin suggests the existence of unexpected molecular players in progranulin-associated neurodegeneration. Show more

Keywords: Frontotemporal dementia, GRN, Kaplan-Meier Survival curves, mutation, pedigrees, plasma, progranulin, SLPI protein

DOI: 10.3233/JAD-131163

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 533-539, 2014

Authors: Tifratene, Karim | Sakarovitch, Charlotte | Rouis, Amel | Pradier, Christian | Robert, Philippe | the participating centers

Article Type: Research Article

Abstract: Unlike Alzheimer's disease (AD), there are no drugs approved for the treatment of mild cognitive impairment (MCI). The objective of this study was to evaluate real world prescriptions of anti-AD medications in patients with MCI in France and to determine characteristics associated with treatment. A cross sectional study of the French National Alzheimer Databank (BNA) was conducted. Patients diagnosed with MCI by physicians of the BNA network in 2010 and 2011 were included in this study. We included 16,236 patients with a diagnosis of MCI in the study. Mean age was 76.4 years old and females were 59.5%. Nine hundred …eighty five patients (6.1%) were taking an anti-AD medication. Results of a multivariate analysis show that use was associated with older age, lower MMSE score, amnestic MCI subtype, living at home, and higher education. Treatment with antidepressant drugs was also associated with anti-AD medication use (odd ratio: 1.68; 95% confidence interval: 1.44 to 1.96). “Off label” prescription of anti-AD drugs is low in France and seems to be limited to a population at risk of conversion to AD. Similar analysis will be required to monitor this practice in the future. Show more

Keywords: Alzheimer's disease, cholinesterase inhibitors, medications, memantine, mild cognitive impairment

DOI: 10.3233/JAD-131103

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 541-549, 2014

Authors: Schmitz, Matthias | Wulf, Katharina | Signore, Sandra C. | Schulz-Schaeffer, Walter J. | Kermer, Pawel | Bähr, Mathias | Wouters, Fred S. | Zafar, Saima | Zerr, Inga

Article Type: Research Article

Abstract: Previous studies indicate an important role for the cellular prion protein (PrPC ) in the development of Alzheimer's disease (AD) pathology. In the present study, we analyzed the involvement of PrPC in different pathological mechanisms underlying AD: the processing of the amyloid-β protein precursor (AβPP) and its interaction with AβPP, tau, and different phosphorylated forms of the tau protein (p-tau). The effect of PrPC on tau expression was investigated in various cellular compartments using a HEK293 cell model expressing a tau mutant (3PO-tau) or wild type (WT)-tau. We could show that PrPC reduces AβPP cleavage, …leading to decreased levels of Aβ40 and sAβPP without changing the protein expression of AβPP, β-secretase, or γ-secretase. Tau and its phosphorylated forms were identified as interactions partners for PrPC , raising the question as to whether PrPC might also be involved in tau pathology. Overexpression of PrPC in PRNP and 3PO-tau transfected cells resulted in a reduction of 3PO-tau and p-tau as well as a decrease of 3PO-tau-related toxicity. In addition, we used the transgenic PrPC knockout (Prnp0/0) mouse line to study the dynamics of tau phosphorylation, an important pathological hallmark in the pathogenesis of AD in vivo. There, an effect of PrPC on tau expression could be observed under oxidative stress conditions but not during aging. In summary, we provide further evidence for interactions of PrPC with proteins that are known to be the key players in AD pathogenesis. We identified tau and its phosphorylated forms as potential PrP-interactors and report a novel protective function of PrPC in AD-like tau pathology. Show more

Keywords: Alzheimer's disease, amyloid, β-secretase, cellular prion protein, neuroprotection, 3PO-tau, p-tau

DOI: 10.3233/JAD-130566

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 551-565, 2014

Authors: Lundström, Susanna L. | Yang, Hongqian | Lyutvinskiy, Yaroslav | Rutishauser, Dorothea | Herukka, Sanna-Kaisa | Soininen, Hilkka | Zubarev, Roman A.

Article Type: Research Article

Abstract: Blood-based anti-amyloid-β (Aβ) immunoglobulins (IgGs) and peripheral inflammation are factors correlating with development of Alzheimer's disease (AD). IgG functionality can drastically change from anti- to pro-inflammatory via alterations in the IgG-Fc N-glycan structure. Herein, we tested if IgG-Fc glycosylation in plasma is indeed altered during the development of AD. Samples from age-matched subjects of 23 controls, 58 patients with stable mild cognitive impairment (SMCI), 34 patients with progressive (P)MCI, and 31 patients with AD were investigated. Label-free shotgun proteomics was applied without glycoprotein enrichment. Glycans on peptides EEQYNSTYR (IgG1 ) and EEQFNSTFR (IgG2 ) were quantified, and their abundances were …normalized to total IgGn glycoform abundance. Univariate and multivariate statistics were employed to investigate the correlations between the patients groups and the abundances of the IgG glycoforms as well as those of inflammatory mediating proteins. Significant differences (p ≤ 0.05) were found, with a lower abundance of complex galactosylated and sialylated forms in AD. For females, a decline in glycoform complexity correlated with disease progress but an inverse change was found in males prior to the onset of AD. Principal component analysis (PCA; Males: R2 X(cum) = 0.65, Q2 (cum) = 0.34; Females: R2 X(cum) = 0.62, Q2 (cum) = 0.36), confirmed the gender similarities (for controls, SMCI and AD) as well as differences (for PMCI), and showed a close correlation between pro-inflammatory protein markers, AD, female PMCI, and truncated IgG-Fc glycans. The differences observed between genders prior to the onset of AD may indicate a lower ability in females to suppress peripheral inflammation, which may lead to exacerbated disease progression. Show more

Keywords: Fc, glycoproteomics, glycosylation, immunoglobulin, inflammation

DOI: 10.3233/JAD-131088

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 567-579, 2014