Journal of Alzheimer's Disease - Volume 57, issue 2

Authors: Delgado-González, José-Carlos | Florensa-Vila, José | Mansilla-Legorburo, Francisco | Insausti, Ricardo | Artacho-Pérula, Emilio

Article Type: Research Article

Abstract: Background: The medial temporal lobe (MTL), and in particular the hippocampal formation, is essential in the processing and consolidation of declarative memory. The 3D environment of the anatomical structures contained in the MTL is an important issue. Objective: Our aim was to explore the spatial relationship of the anatomical structures of the MTL and changes in aging and/or Alzheimer’s disease (AD). Methods: MTL anatomical landmarks are identified and registered to create a 3D network. The brain network is quantitatively described as a plane, rostrocaudally-oriented, and presenting Euclidean/real distances. Correspondence between 1.5T RM, 3T RM, and …histological sections were assessed to determine the most important recognizable changes in AD, based on statistical significance. Results: In both 1.5T and 3T RM images and histology, inter-rater reliability was high. Sex and hemisphere had no influence on network pattern. Minor changes were found in relation to aging. Distances from the temporal pole to the dentate gyrus showed the most significant differences when comparing control and AD groups. The best discriminative distance between control and AD cases was found in the temporal pole/dentate gyrus rostrocaudal length in histological sections. Moreover, more distances between landmarks were required to obtain 100% discrimination between control (divided into <65 years or >65 years) and AD cases. Discussion: Changes in the distance between MTL anatomical landmarks can successfully be detected by using measurements of 3D network patterns in control and AD cases. Show more

Keywords: Alzheimer’s disease, Euclidean distances, histology, magnetic resonance imaging, medial temporal lobe

DOI: 10.3233/JAD-160944

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 461-473, 2017

Authors: Yu, Lixia | Wang, Weiguang | Pang, Wei | Xiao, Zhonghai | Jiang, Yugang | Hong, Yan

Article Type: Research Article

Abstract: Background: Oxidative stress is implicated in the pathogenesis of Alzheimer’s disease (AD) and other tauopathies and participates in their development by promoting hyperphosphorylation of microtubule-associated protein tau. Lycopene, as an effective antioxidant, combined with vitamin E seemed to be additive against oxidative stress. Objective: The present study was undertaken to examine whether lycopene or lycopene/vitamin E could exert protective effects on memory deficit and oxidative stress in tau transgenic mice expressing P301L mutation. Materials and methods: P301L transgenic mice were assigned to three groups: P301L group (P301L), P301L+lycopene (Lyc), and P301L+lycopene/vitamin E (Lyc+VE). Age-matched C57BL/6J …mice as wild type controls (Con) were used in the present study. Spatial memory was assessed by radial arm while passive memories were evaluated by step-down and step-through tests. Levels of tau phosphorylation were detected by western blot. Oxidative stress biomarkers were measured in the serum using biochemical assay kits. Results: Compared with the control group, P301L mice displayed significant spatial and passive memory impairments, elevated malondialdehyde (MDA) levels and decreased glutathione peroxidase (GSH-Px) activities in serum, and increased tau phosphorylation at Thr231/Ser235, Ser262, and Ser396 in brain. Supplementations of lycopene or lycopene/vitamin E could significantly ameliorate the memory deficits, observably decreased MDA concentrations and increased GSH-Px activities, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites. Conclusions: Our findings indicated that the combination of lycopene and vitamin E antioxidants acted in a synergistic fashion to bring significant effects against oxidative stress in tauopathies. Show more

Keywords: Lycopene, oxidative stress, P301L tau protein, phosphorylation, spatial memory, vitamin E

DOI: 10.3233/JAD-161216

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 475-482, 2017

Authors: Riancho, Javier | Vázquez-Higuera, José Luis | Pozueta, Ana | Lage, Carmen | Kazimierczak, Martha | Bravo, María | Calero, Miguel | Gonalezález, Andrea | Rodríguez, Eloy | Lleó, Alberto | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: Background: MicroRNAs have been postulated as potential biomarkers for Alzheimer’s disease (AD). Exosomes are nanovesicles which transport microRNAs, proteins, and other cargos. It has been hypothesized that the exosome traffic might be increased in neurodegenerative disorders. Objective: i) To assess the cerebrospinal fluid (CSF) microRNA profile in a group of AD patients and control subjects and to validate a group of microRNAs previously reported by other authors. ii) To compare microRNA levels in whole CSF and in the exosome-enriched fraction in AD patients. Methods: A panel of 760 microRNAs was analyzed in the CSF of …10 AD patients and 10 healthy subjects. Among microRNAs differently expressed, we selected those that had been previously reported by other authors. Candidates were validated in a larger group by individual qPCR assays. MicroRNA expression was also evaluated in exosome-enriched CSF samples of patients with AD and controls. Results: Fifteen microRNAs were differently expressed in AD. MiR-9-5p, miR-134, and miR-598 were selected as candidates for further analysis. MiR-9-5p and miR-598 were detected in 50 and 75% of control CSF samples, respectively, while they were not detected in any AD CSF samples. We observed an opposite pattern when we evaluated the microRNA expression in the exosome-enriched CSF AD samples. No pattern variations were noted among healthy subjects. Conclusion: These data propose miR-9-5p and miR-598 as potential biomarkers for AD. Further studies in plasma and other body fluids will confirm their potential role as easily accessible biomarkers. In addition, our data suggest that exosome trafficking is different between AD and control subjects raising the need to take this phenomenon into consideration in future studies of AD biomarkers. Show more

Keywords: Alzheimer’s disease, biomarkers, exosomes, microRNAs

DOI: 10.3233/JAD-161179

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 483-491, 2017

Authors: Oberacher, Herbert | Arnhard, Kathrin | Linhart, Caroline | Diwo, Angela | Marksteiner, Josef | Humpel, Christian

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system. The use of biological fluids in AD diagnosis remains limited to the analysis of specific protein biomarkers in cerebrospinal fluid. However, metabolomic analysis has recently revealed several metabolites in plasma, especially phosphatidylcholines (PC), as putative biomarkers specific for AD. Following on previous reports of platelet abnormalities in AD, we hypothesized that platelets metabolites released in plasma may offer new biomarkers in AD. The aim of the present study was to apply targeted metabolomics to compare metabolites in soluble lysates of platelets from healthy controls (CO), patients with …mild cognitive impairment (MCI), and patients with AD in a cohort of 90 subjects. We could target 163 metabolites and quantitative data were obtained for 91 metabolites. Among these, the lipid PC aeC40:4 significantly differentiated AD from CO (p  = 0.0009), while four other lipids (PC aaC32:0, PC ae C32:2, PC aeC34:1, and SM(OH)C14:1) differentiated patients with MCI from CO. The combination of three phosphatidylcholines (PC aeC32:2, PC aeC34:1, PCaaC36:5), two lyso-phosphatidylcholines (lysoPC aC18:1, lysoPC aC16:0), and one sphingomyelin (SM(OH) C14:1) constructed a valuable prediction model using the C4.5 decision tree. The diagnosis accuracy for AD versus CO and MCI was 85%. In a blinded follow up conversion study (10 patients with a second blood collection after 9 months), we could verify the clinical diagnosis in 19 out of 20 cases. We propose that soluble platelet PCaeC40:4 is a promising marker to diagnose AD with a cut-off of <0.30μM and that platelets undergo metabolic processes during AD progression. Show more

Keywords: Alzheimer’s disease, biomarkers, diagnosis, metabolomics, platelets

DOI: 10.3233/JAD-160172

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 493-504, 2017

Authors: Zhang, Ce | Zhang, Yiying | Shen, Yuan | Zhao, Guoqing | Xie, Zhongcong | Dong, Yuanlin

Article Type: Research Article

Abstract: Anesthesia and/or surgery may promote Alzheimer’s disease (AD) by accelerating its neuropathogenesis. Other studies showed different findings. However, the potential sex difference among these studies has not been well considered, and it is unknown whether male or female AD patients are more vulnerable to develop postoperative cognitive dysfunction. We therefore set out to perform a proof of concept study to determine whether anesthesia and surgery can have different effects in male and female AD transgenic (Tg) mice, and in female AD Tg plus Cyclophilin D knockout (CypD KO) mice. The mice received an abdominal surgery under sevoflurane anesthesia (anesthesia/surgery). Fear …Conditioning System (FCS) was used to assess the cognitive function. Hippocampal levels of synaptic marker postsynaptic density 95 (PSD-95) and synaptophysin (SVP) were measured using western blot analysis. Here we showed that the anesthesia/surgery decreased the freezing time in context test of FCS at 7 days after the anesthesia/surgery in female, but not male, mice. The anesthesia/surgery reduced hippocampus levels of synaptic marker PSD-95 and SVP in female, but not male, mice. The anesthesia/surgery induced neither reduction in freezing time in FCS nor decreased hippocampus levels of PSD-95 and SVP in the AD Tg plus CypD KO mice. These data suggest that the anesthesia/surgery induced a sex-dependent cognitive impairment and reduction in hippocampus levels of synaptic markers in AD Tg mice, potentially via a mitochondria-associated mechanism. These findings could promote clinical investigations to determine whether female AD patients are more vulnerable to the development of postoperative cognitive dysfunction. Show more

Keywords: Alzheimer’s disease, cognitive function, cyclophilin D, sevoflurane, surgery, synaptic marker

DOI: 10.3233/JAD-161268

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 505-518, 2017

Authors: Heuer, Eric | Jacobs, Jessica | Du, Rebecca | Wang, Silun | Keifer Jr., Orion P. | Cintron, Amarallys F. | Dooyema, Jeromy | Meng, Yuguang | Zhang, Xiaodong | Walker, Lary C.

Article Type: Research Article

Abstract: Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimer’s disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility weighted images. ARIA in general has been linked to the presence of amyloid-β (Aβ)-type cerebral amyloid angiopathy, an accumulation of misfolded Aβ protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of …ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus ), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-beta, amyloid-related imaging abnormalities, ARIA-E, ARIA-H, inflammation, immunotherapy, magnetic resonance imaging, vascular disease

DOI: 10.3233/JAD-160981

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 519-530, 2017

Authors: van der Ven, Amelie T. | Pape, Julius C. | Hermann, Dirk | Schloesser, Robert | Genius, Just | Fischer, Nadine | Mößner, Rainald | Scherbaum, Norbert | Wiltfang, Jens | Rujescu, Dan | Benninghoff, Jens

Article Type: Research Article

Abstract: An interest in neurogenesis in the adult human brain as a relevant and targetable process has emerged as a potential treatment option for Alzheimer’s disease and other neurodegenerative conditions. The aim of this study was to investigate the effects of tetramethylthionine chloride (methylene blue, MB) on properties of adult murine neural stem cells. Based on recent clinical studies, MB has increasingly been discussed as a potential treatment for Alzheimer’s disease. While no differences in the proliferative capacity were identified, a general potential of MB in modulating the migratory capacity of adult neural stem cells was indicated in a cell mobility …assay. To our knowledge, this is the first time that MB could be associated with neural mobility. The results of this study add insight to the spectrum of features of MB within the central nervous system and may be helpful for understanding the molecular mechanisms underlying a potential therapeutic effect of MB. Show more

Keywords: Adult stem cells, Alzheimer’s disease, methylene blue, neural plasticity

DOI: 10.3233/JAD-160755

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 531-540, 2017

Authors: De Marco, Matteo | Duzzi, Davide | Meneghello, Francesca | Venneri, Annalena

Article Type: Research Article

Abstract: There are cognitive domains which remain fully functional in a proportion of Alzheimer’s disease (AD) patients. It is unknown, however, what distinctive mechanisms sustain such efficient processing. The concept of “cognitive efficiency” was investigated in these patients by operationalizing it as a function of the level of performance shown on the Letter Fluency test, on which, very often, patients in the early stages of AD show unimpaired performance. Forty-five individuals at the prodromal/early stage of AD (diagnosis supported by subsequent clinical follow-ups) and 45 healthy controls completed a battery of neuropsychological tests and an MRI protocol which included resting state …acquisitions. The Letter Fluency test was the only task on which no between-group difference in performance was found. Participants were divided into “low-performing” and “high-performing” according to the global median. Dual-regression methods were implemented to compute six patterns of network connectivity. The diagnosis-by-level of performance interaction was inferred on each pattern to determine the network distinctiveness of efficient performance in AD. Significant interactions were found in the anterior default mode network, and in both left and right executive control networks. For all three circuits, high-performing patients showed increased connectivity within the ventral and dorsal part of BA19, as confirmed by post hoc t tests . Peristriate remapping is suggested to play a compensatory role. Since the occipital lobe is the neurophysiological source of long-range cortical connectivity, it is speculated that the physiological mechanisms of functional connectivity might sustain occipital functional remapping in early AD, particularly for those functions which are sustained by areas not excessively affected by the prodromal disease. Show more

Keywords: Alzheimer’s disease, cuneus, cognitive function, magnetic resonance imaging

DOI: 10.3233/JAD-161164

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 541-556, 2017

Authors: Ketter, Nzeera | Brashear, H. Robert | Bogert, Jennifer | Di, Jianing | Miaux, Yves | Gass, Achim | Purcell, Derk D. | Barkhof, Frederik | Arrighi, H. Michael

Article Type: Research Article

Abstract: Background: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). Objectives: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer’s disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ 4 allele carriers or noncarriers). Methods: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ 4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is …described. Results: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ 4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. Conclusion: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study. Show more

Keywords: Alzheimer’s disease, bapineuzumab, brain amyloid-related imaging abnormality, magnetic resonance imaging Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302)

DOI: 10.3233/JAD-160216

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 557-573, 2017

Authors: Dallaire-Théroux, Caroline | Callahan, Brandy L. | Potvin, Olivier | Saikali, Stéphan | Duchesne, Simon

Article Type: Research Article

Abstract: Background: The standard method of ascertaining Alzheimer’s disease (AD) remains postmortem assessment of amyloid plaques and neurofibrillary degeneration. Vascular pathology, Lewy bodies, TDP-43, and hippocampal sclerosis are frequent comorbidities. There is therefore a need for biomarkers that can assess these etiologies and provide a diagnosis in vivo . Objective: We conducted a systematic review of published radiological-pathological correlation studies to determine the relationship between antemortem magnetic resonance imaging (MRI) and neuropathological findings in AD. Methods: We explored PubMed in June-July 2015 using “Alzheimer’s disease” and combinations of radiological and pathological terms. After exclusion following screening …and full-text assessment of the 552 extracted manuscripts, three others were added from their reference list. In the end, we report results based on 27 articles. Results: Independently of normal age-related brain atrophy, AD pathology is associated with whole-brain and hippocampal atrophy and ventricular expansion as observed on T1-weighted images. Moreover, cerebral amyloid angiopathy and cortical microinfarcts are also related to brain volume loss in AD. Hippocampal sclerosis and TDP-43 are associated with hippocampal and medial temporal lobe atrophy, respectively. Brain volume loss correlates more strongly with tangles than with any other pathological finding. White matter hyperintensities observed on proton density, T2-weighted and FLAIR images are strongly related to vascular pathologies, but are also associated with other histological changes such as gliosis or demyelination. Conclusion: Cerebral atrophy and white matter changes in the living brain reflect underlying neuropathology and may be detectable using antemortem MRI. In vivo MRI may therefore be an avenue for AD pathological staging. Show more

Keywords: Alzheimer’s disease, antemortem diagnosis, dementia, magnetic resonance imaging, neuroimaging, neuropathology

DOI: 10.3233/JAD-161028

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 575-601, 2017