Journal of Alzheimer's Disease - Volume 43, issue 3

Authors: Glodzik, Lidia | Sollberger, Marc | Gass, Achim | Gokhale, Amit | Rusinek, Henry | Babb, James. S. | Hirsch, Jochen G. | Amann, Michael | Monsch, Andreas U. | Gonen, Oded

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is an intermediary state on the way to Alzheimer's disease (AD). Little is known about whole brain concentration of the neuronal marker, N-acetylaspartate (NAA) in MCI patients. Objective: To test the hypothesis that since MCI and AD are both neurodegenerative, quantification of the NAA in their whole brain (WBNAA) could differentiate them from cognitively-intact matched controls. Methods: Proton MR spectroscopy to quantify the WBNAA was applied to 197 subjects (86 females) 72.6 ± 8.4 years old (mean ± standard deviation). Of these, 102 were cognitively intact, 42 diagnosed as MCI, and …53 as probable AD. Their WBNAA amounts were converted into absolute concentration by dividing with the brain volume segmented from the MRI that also yielded the fractional brain volume (fBPV), an atrophy metric. Results: WBNAA concentration of MCI and AD patients (10.5 ± 3.0 and 10.1 ± 2.9 mM) were not significantly different (p = 0.85). They were, however, highly significantly 25–29% lower than the 14.1 ± 2.4 mM of normal matched controls (p < 10−4 ). The fBPV of MCI and AD patients (72.9 ± 4.9 and 69.9 ± 4.7%) differed significantly from each other (4%, p = 0.02) and both were significantly lower than the 74.6 ± 4.4% of normal elderly (2%, p = 0.003 for MCI; 6%, p < 10−4 for AD). ROC curve analysis has shown WBNAA to have 70.5% sensitivity and 84.3% specificity to differentiate MCI or AD patients from normal elderly versus just 68.4 and 65.7% for fBPV. Conclusion: Low WBNAA in MCI patients compared with cognitively normal contemporaries may indicate early neuronal damage accumulation and supports the notion of MCI as an early stage of AD. It also suggests WBNAA as a potential marker of early AD pathology. Show more

Keywords: Alzheimer's disease, magnetic resonance spectroscopy, mild cognitive impairment, N-acetylaspartate, normal aging

DOI: 10.3233/JAD-140609

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 939-947, 2015

Authors: Liu-Seifert, Hong | Siemers, Eric | Sundell, Karen | Price, Karen | Han, Baoguang | Selzler, Katherine | Aisen, Paul | Cummings, Jeffrey | Raskin, Joel | Mohs, Richard

Article Type: Research Article

Abstract: Background: In patients with Alzheimer's disease (AD), the relationship between cognitive and functional progression is not fully understood; however, functional decline has been postulated to follow cognitive decline. Objective: To assess the relationship between cognitive and functional treatment effects in mild AD dementia patients. Methods: Data of patients with mild AD were pooled from two multicenter, double-blind, Phase 3 studies. Patients were randomized to infusions of 400-mg solanezumab (n = 654), or placebo (n = 660) every 4 weeks for 18 months. Cognitive and functional outcome measures were assessed using the AD Assessment Scale-Cognitive subscale (ADAS-Cog) …and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL), respectively. Analyses included comparisons among normalized scales, correlations between outcome measures, and path analyses to model the relationship of treatment effect on cognition and function. Results: Normalized ADAS-Cog and ADCS-ADL scales showed cognitive impairment was more evident than functional impairment in mild AD. The correlation between cognition and function increased over time. Path analyses demonstrated that 87% of the treatment effect on function was driven by the treatment effect on cognition, with the remaining 13% due to direct treatment effect. Conclusion: Findings from this study are consistent with the hypothesis that functional impairment is primarily driven by and follows cognitive decline in mild AD dementia. The cognitive treatment effect appeared to explain the majority of the functional treatment effect. It is possible that a cognitive treatment effect may be considered as a leading indicator for functional outcomes in an 18-month clinical trial for milder stages of AD. Show more

Keywords: Activities of daily living, Alzheimer's disease, clinical trials, cognition, correlation of data, dementia, Phase 3, solanezumab

DOI: 10.3233/JAD-140792

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 949-955, 2015

Authors: Maheshwari, Priya | Eslick, Guy D.

Article Type: Research Article

Abstract: The possibility of an infectious etiology for Alzheimer's disease (AD) has been repeatedly postulated over the past three decades. We provide the first meta-analysis to address the relationship between bacterial infection and AD. Studies examining the association between AD and spirochetal bacteria or Chlamydophila pneumoniae (Cpn) were identified through a systematic search of the databases MEDLINE, EMBASE, PubMed, and Google Scholar. Data combined from 25 relevant, primarily case-control studies demonstrated a statistically significant association between AD and detectable evidence of infection of either bacterial group. We found over a ten-fold increased occurrence of AD when there is detectable evidence of …spirochetal infection (OR: 10.61; 95% CI: 3.38–33.29) and over a four-fold increased occurrence of AD in a conservative risk estimate (OR: 4.45; 95% CI: 2.33–8.52). We found over a five-fold increased occurrence of AD with Cpn infection (OR: 5.66; 95% CI: 1.83–17.51). This study shows a strongly positive association between bacterial infection and AD. Further detailed investigation of the role of bacterial infection is warranted. Show more

Keywords: Alzheimer's disease, bacteria, Borrelia, Chlamydophila, dementia, etiology, infection, inflammation, Spirochaetales, Treponema

DOI: 10.3233/JAD-140621

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 957-966, 2015

Authors: Campbell, Shannon N. | Zhang, Cheng | Monte, Louise | Roe, Allyson D. | Rice, Kenner C. | Taché, Yvette | Masliah, Eliezer | Rissman, Robert A.

Article Type: Research Article

Abstract: Clinical and basic science research suggests that stress and/or changes in central stress signaling intermediates may be involved in Alzheimer's disease (AD) pathogenesis. Although the links between stress and AD remain unsettled, data from our group and others have established that stress exposure in rodents may confer susceptibility to AD pathology by inducing hippocampal tau phosphorylation (tau-P). Work in our laboratory has shown that stress-induced tau-P requires activation of the type-1 corticotropin-releasing factor receptor (CRFR1). CRF overexpressing (CRF-OE) mice are a model of chronic stress that display cognitive impairment at 9–10 month of age. In this study we used 6–7 …month old CRF-OE mice to examine whether sustained exposure to CRF and stress steroids would impact hippocampal tau-P and kinase activity in the presence or absence of the CRFR1-specific antagonist, R121919, given daily for 30 days. CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202 /T204 ), PHF-1 (S396/404 ), S262 , and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202 /T204 ) and PHF-1 (S396/404 ) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK). Examination of hippocampal extracts from CRF-OE mice at the ultrastructural level revealed negatively stained round/globular aggregates that were positively labeled by PHF-1. These data suggest critical roles for CRF and CRFR1 in tau-P and aggregation and may have implications for the development of AD cognitive decline. Show more

Keywords: Alzheimer's disease, corticotropin-releasing factor (CRF), corticotropin-releasing factor receptor (CRFR), electron microscopy, hippocampus, immunohistochemistry, stress, tau phosphorylation (tau-P), western blot

DOI: 10.3233/JAD-141281

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 967-976, 2015

Authors: Aso, Ester | Sánchez-Pla, Alexandre | Vegas-Lozano, Esteban | Maldonado, Rafael | Ferrer, Isidro

Article Type: Research Article

Abstract: Several recent findings suggest that targeting the endogenous cannabinoid system can be considered as a potential therapeutic approach to treat Alzheimer's disease (AD). The present study supports this hypothesis demonstrating that delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) botanical extracts, as well as the combination of both natural cannabinoids, which are the components of an already approved cannabis-based medicine, preserved memory in AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Moreover, THC + CBD reduced learning impairment in AβPP/PS1 mice. A significant decrease in soluble Aβ42 peptide levels and a change in plaques composition were also observed in …THC + CBD-treated AβPP/PS1 mice, suggesting a cannabinoid-induced reduction in the harmful effect of the most toxic form of the Aβ peptide. Among the mechanisms related with these positive cognitive effects, the anti-inflammatory properties of cannabinoids may also play a relevant role. Here we observed reduced astrogliosis, microgliosis, and inflammatory-related molecules in treated AβPP/PS1 mice, which were more marked after treatment with THC + CBD than with either THC or CBD. Moreover, other cannabinoid-induced effects were uncovered by a genome-wide gene expression study. Thus, we have identified the redox protein thioredoxin 2 and the signaling protein Wnt16 as significant substrates for the THC + CBD-induced effects in our AD model. In summary, the present findings show that the combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD. Show more

Keywords: Alzheimer's disease, animal model, cannabidiol, tetrahydrocannabinol, therapy

DOI: 10.3233/JAD-141014

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 977-991, 2015

Authors: Saad, Yaara | Segal, Daniel | Ayali, Amir

Article Type: Research Article

Abstract: Though it is widely accepted that amyloid-β (Aβ) is a key factor in Alzheimer's disease (AD) pathology, its underlying mechanism remains unclear. In order to study the association between Aβ and neural circuitry dysfunction, we developed a primary culture preparation derived from the nervous system of transgenic Drosophila melanogaster larvae expressing human Aβ1-42 (Aβ42 ). Cultured neurons undergo a consistent developmental process, culminating in an elaborate neuronal network with distinct functional and morphological characteristics. Throughout this development, a time-dependent increase in intracellular expression levels of Aβ42 was detected, followed by extracellular staining at a later time point. When …compared to controls, Aβ42 cultures exhibited enhanced levels of apoptosis, resulting in reduced cell viability. Moreover, as primary culture preparations enable high resolution monitoring of neuronal phenotypes, we were able to detect subtle morphological changes in neurons expressing Aβ42 , namely an enhancement in neurite outgrowth and arborization, which preceded the effect of neurodegeneration. Our results establish D. melanogaster primary neuronal cultures as a rapid, accessible and cost-effective platform for AD molecular studies and drug screening, and suggest a possible role for Aβ42 in the organization of neuronal processes. Show more

Keywords: Alzheimer's disease, amyloid-β, drosophila, neural network, primary cell culture

DOI: 10.3233/JAD-140009

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 993-1006, 2015

Authors: Mackin, R. Scott | Insel, Philip | Zhang, Jing | Mohlenhoff, Brian | Galasko, Douglas | Weiner, Michael | Mattsson, Niklas | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer's disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD. Objective: Determine associations between CSF α-synuclein and Lewy body-like symptomatology. Methods: We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6–7.8). We tested associations between baseline CSF α-synuclein …and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration. Results: Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI). Conclusion: The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification. Show more

Keywords: Alpha-synuclein, Alzheimer's disease, cerebrospinal fluid, cognition, hallucinations, tau

DOI: 10.3233/JAD-141287

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1007-1016, 2015

Authors: Zhao, Hua | Li, Hongyun | Ruberu, Kalani | Garner, Brett

Article Type: Research Article

Abstract: Cobalamin (vitamin B12) is required for erythrocyte formation and DNA synthesis and it plays a crucial role in maintaining neurological function. As a coenzyme for methionine synthase and methylmalonyl-CoA mutase, cobalamin utilization depends on its efficient transit through the intracellular lysosomal compartment and subsequent delivery to the cytosol and mitochondria. Lysosomal function deteriorates in Alzheimer's disease (AD). Lysosomal acidification is defective in AD and lysosomal proteolysis is disrupted by AD-related presenilin 1 mutation. In this study, we propose that AD related lysosomal dysfunction may impair lysosomal cobalamin transport. The experiments use in vitro and in vivo models of AD to …define how lysosomal dysfunction directly affects cobalamin utilization. SH-SY5Y-AβPP mutant cells were treated with a proteasome inhibitor to induce lysosomal amyloid-β accumulation. We metabolically labeled these cells with [57 Co] cobalamin and isolated purified lysosomes, mitochondria, and cytosol fractions. The results indicated that proteasome inhibition was associated with lysosomal amyloid-β accumulation and a doubling of lysosomal [57 Co] cobalamin levels. We also used AβPPxPS1 transgenic AD mice that were intraperitoneally injected with [57 Co] cobalamin. The amount of [57 Co] cobalamin in the major organs of these mice was measured and the subcellular [57 Co] cobalamin distribution in the brain was assessed. The results demonstrated that lysosomal [57 Co] cobalamin level was significantly increased by 56% in the AβPPxPS1 AD mouse brains as compared to wild type control mice. Together these data provide evidence that lysosomal cobalamin may be impaired in AD in association with amyloid-β accumulation. Show more

Keywords: Alzheimer's disease, amyloid-β, lysosomes, neurodegeneration, vitamin B12

DOI: 10.3233/JAD-140681

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1017-1030, 2015

Authors: Mroczko, Barbara | Groblewska, Magdalena | Zboch, Marzena | Muszyński, Paweł | Zajkowska, Agata | Borawska, Renata | Szmitkowski, Maciej | Kornhuber, Johannes | Lewczuk, Piotr

Article Type: Research Article

Abstract: Background: The correlations between pathology of neurodegenerative diseases, especially Alzheimer's disease (AD), and concentrations of neuronal calcium sensor proteins, such as visinin-like protein 1 (VILIP-1), in cerebrospinal fluid (CSF) have been discussed in the literature but its utility as biomarker of AD in comparison with mild cognitive impairment (MCI) has not been studied yet. Objective: Therefore, the aim of our study was to assess the clinical utility of the measurement of CSF concentrations of VILIP-1 in patients with AD, MCI subjects, and non-demented controls. The clinical and neuropsychological diagnoses were supported by CSF biomarkers of neurochemical dementia diagnostics: …decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio and increased concentrations of Tau and pTau181 proteins. Methods: The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of biomarkers tested were determined by using the ELISA method. Results: Concentrations of VILIP-1 in CSF were significantly higher in AD patients compared to the MCI subjects and elderly individuals without cognitive impairment. Increased concentrations of VILIP-1 correlated significantly with reduced Aβ42/40 ratio and higher pTau181 in AD group. Conclusion: Our findings suggest that VILIP-1 may play a role in the AD pathophysiology and is a good candidate for dynamic biomarker of AD, although this issue requires further investigation. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, mild cognitive impairment, visinin-like protein 1

DOI: 10.3233/JAD-141050

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1031-1037, 2015

Authors: Calderón-Garcidueñas, Lilian | Vojdani, Aristo | Blaurock-Busch, Eleonore | Busch, Yvette | Friedle, Albrecht | Franco-Lira, Maricela | Sarathi-Mukherjee, Partha | Martínez-Aguirre, Xavier | Park, Su-Bin | Torres-Jardón, Ricardo | D'Angiulli, Amedeo

Article Type: Research Article

Abstract: Millions of children are exposed to concentrations of air pollutants, including fine particulate matter (PM2.5 ), above safety standards. In the Mexico City Metropolitan Area (MCMA) megacity, children show an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and blood-brain barrier breakdown. We investigated serum and cerebrospinal fluid (CSF) antibodies to neural and tight junction proteins and environmental pollutants in 139 children ages 11.91 ± 4.2 y with high versus low air pollution exposures. We also measured metals in serum and CSF. MCMA children showed significantly higher serum actin IgG, occludin/zonulin 1 IgA, IgG, myelin …oligodendrocyte glycoprotein IgG and IgM (p < 0.01), myelin basic protein IgA and IgG, S-100 IgG and IgM, and cerebellar IgG (p < 0.001). Serum IgG antibodies to formaldehyde, benzene, and bisphenol A, and concentrations of Ni and Cd were significantly higher in exposed children (p < 0.001). CSF MBP antibodies and nickel concentrations were higher in MCMA children (p = 0.03). Air pollution exposure damages epithelial and endothelial barriers and is a robust trigger of tight junction and neural antibodies. Cryptic ‘self’ tight junction antigens can trigger an autoimmune response potentially contributing to the neuroinflammatory and Alzheimer and Parkinson's pathology hallmarks present in megacity children. The major factor determining the impact of neural antibodies is the integrity of the blood-brain barrier. Defining the air pollution linkage of the brain/immune system interactions and damage to physical and immunological barriers with short and long term neural detrimental effects to children's brains ought to be of pressing importance for public health. Show more

Keywords: Air pollution, Alzheimer's disease, children, innate and adaptive immunity, neurodegeneration, neuroinflammation, particulate matter, tight junction and neural reactive autoantibodies

DOI: 10.3233/JAD-141365

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1039-1058, 2015

Authors: Ferreira, Daniel | Westman, Eric | Eyjolfsdottir, Helga | Almqvist, Per | Lind, Göran | Linderoth, Bengt | Seiger, Åke | Blennow, Kaj | Karami, Azadeh | Darreh-Shori, Taher | Wiberg, Maria | Simmons, Andrew | Wahlund, Lars-Olof | Wahlberg, Lars | Eriksdotter, Maria | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: New therapies with disease-modifying effects are urgently needed for treating Alzheimer's disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. …Patients were grouped as responders and non-responders according to their twelve-months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age- and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at baseline indicated that responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Aβ1-42 . However, they showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments. At follow-up, responders showed less brain shrinkage and better progression in the clinical variables and CSF biomarkers. Noteworthy, two responders showed less brain shrinkage than the normative ADNI group. These results together with previous evidence supports the idea that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD with both symptomatic and disease-modifying effects. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid biomarkers, clinical progression, clinical trial, encapsulated cell biodelivery, nerve growth factor, neurofilaments, structural MRI, ADNI, brain changes

DOI: 10.3233/JAD-141068

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1059-1072, 2015

Authors: Scheff, Stephen W. | Price, Douglas A. | Ansari, Mubeen A. | Roberts, Kelly N. | Schmitt, Frederick A. | Ikonomovic, Milos D. | Mufson, Elliott J.

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is considered to be an early stage in the progression of Alzheimer's disease (AD) providing an opportunity to investigate brain pathogenesis prior to the onset of dementia. Neuroimaging studies have identified the posterior cingulate gyrus (PostC) as a cortical region affected early in the onset of AD. This association cortex is involved in a variety of different cognitive tasks and is intimately connected with the hippocampal/entorhinal cortex region, a component of the medial temporal memory circuit that displays early AD pathology. We quantified the total number of synapses in lamina 3 of the PostC using unbiased …stereology coupled with electron microscopy from short postmortem autopsy tissue harvested from cases at different stage of AD progression. Individuals in the early stages of AD showed a significant decline in synaptic numbers compared to individuals with no cognitive impairment (NCI). Subjects with MCI exhibited synaptic numbers that were between the AD and NCI cohorts. Adjacent tissue was evaluated for changes in both pre and postsynaptic proteins levels. Individuals with MCI demonstrated a significant loss in presynaptic markers synapsin-1 and synaptophysin and postsynaptic markers PSD-95 and SAP-97. Levels of [3 H]PiB binding was significantly increased in MCI and AD and correlated strongly with levels of synaptic proteins. All synaptic markers showed a significant association with Mini-Mental Status Examination scores. These results support the idea that the PostC synaptic function is affected during the prodromal stage of the disease and may underlie some of the early clinical sequelae associated with AD. Show more

Keywords: Alzheimer's disease, dementia, memory, mild cognitive impairment, synapses

DOI: 10.3233/JAD-141518

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1073-1090, 2015

Article Type: Book Review

DOI: 10.3233/JAD-142697

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1091-1092, 2015

Article Type: Other

DOI: 10.3233/JAD-141519

Citation: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 1093-1095, 2015