Journal of Alzheimer's Disease - Volume 54, issue 2

Authors: Marchesi, Nicoletta | Amadio, Marialaura | Colombrita, Claudia | Govoni, Stefano | Ratti, Antonia | Pascale, Alessia

Article Type: Research Article

Abstract: Neuronal ELAV/Hu (nELAV) are RNA-binding proteins that mainly regulate gene expression by increasing the stability and/or translation rate of target mRNAs bearing ARE (adenine and uracil-rich elements) sequences. Among nELAV target transcripts there is ADAM10, an α -secretase involved in the non-amyloidogenic processing of the amyloid-β protein precursor (AβPP) which leads to the production of the neuroprotective sAβPPα peptide. The aim of this study was to evaluate if nELAV depletion affects ADAM10 expression in human SH-SY5Y neuroblastoma cells. We also studied the effects of Bryostatin-1, a molecule able to activate nELAV protein cascade. The specific HuD/nELAV gene silencing decreased …both nELAV and ADAM10 protein contents; similar results were obtained by Aβ40 treatment in wild-type SH-SY5Y cells. In HuD-silenced cells, the exposure to Bryostatin-1 counteracted both nELAV and ADAM10 proteins downregulation, by restoring nELAV/ADAM10 basal levels. We also found that sAβPPα release, which seemed not to be compromised by Aβ40 challenge or HuD-silencing, was favored by Bryostatin-1. Overall, these findings strongly suggest that a deficiency in nELAV content negatively affects ADAM10 expression and may play a role in neurodegenerative diseases, which may benefit by molecules activating ELAV cascade. Show more

Keywords: ADAM10, amyloid-β, Bryostatin-1, HuD silencing, nELAV, sAβPPα

DOI: 10.3233/JAD-160299

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 535-547, 2016

Authors: Midorikawa, Akira | Leyton, Cristian E. | Foxe, David | Landin-Romero, Ramon | Hodges, John R. | Piguet, Olivier

Article Type: Research Article

Abstract: Background: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. Objective: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). Methods: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated …the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. Results: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. Conclusions: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, caregivers, factor analysis, frontotemporal dementia, progression, questionnaire development

DOI: 10.3233/JAD-160440

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 549-558, 2016

Authors: Seo, Eun Hyun | Kim, Sang Hoon | Park, Sang Hag | Kang, Seong-Ho | Choo, IL Han | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: APOE ɛ4 contributes to Alzheimer’s disease (AD) pathogenesis by amyloid-beta (Aβ)-dependent and Aβ-independent processes. Objective: We investigated the APOE ɛ4 influence on regional cerebral glucose metabolism (rCMglc) in the continuum of AD after Aβ adjustment. Methods: We included 318 cognitively normal (CN) elderly, 498 mild cognitive impairment (MCI), and 178 AD from the Alzheimer’s Disease Neuroimaging Initiative database. They had [18 F] florbetapir positron emission tomography (PET) and [18 F] fluorodeoxyglucose (FDG)-PET conducted within 3 months of a clinical and cognitive assessment visit and APOE genotype. At first, the rCMglc differences between APOE ɛ4 …carriers (ɛ4+) and non-carriers (ɛ4–) were estimated on a voxel-based analysis using a ‘two-sample t -test’ design. In the second analysis, Aβ was added as covariate. Results: In CN, ɛ4+ showed reduced rCMglc compared to ɛ4–in the bilateral frontal, temporal, and the left parietal regions. In MCI, ɛ4+ showed reduced rCMglc compared to ɛ4– in the bilateral posterior parietal, temporal, and left frontal regions. In AD, ɛ4+ showed reduced rCMglc in the left hippocampus, right insular, and right temporal gyrus. However, after Aβ adjustment, the significant differences in the temporal regions were absent in CN and MCI, and none of the areas detected as significant in the first analysis were statistically significant in AD. Conclusions: Our study demonstrated that Aβ-independent APOE ɛ4 influence on rCMglc is limited to the parietal and frontal, but not temporal lobes. These results suggest that APOE ɛ4 may predispose for regional vulnerability according to Aβ-independent and Aβ-dependent processes. Show more

Keywords: Aβ burden, APOE, cerebral glucose metabolism, mild cognitive impairment

DOI: 10.3233/JAD-160395

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 559-568, 2016

Authors: Fu, YuHong | Hsiao, Jen-Hsiang T. | Paxinos, George | Halliday, Glenda M. | Kim, Woojin Scott

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-β in the brain. Recent genome-wide association studies have revealed that ABCA7 is strongly associated with AD. In vitro evidence suggests that the role of ABCA7 is related to phagocytic activity. Deletion of ABCA7 in a mouse model of AD exacerbates cerebral amyloid-β plaque load. However, the biological role of ABCA7 in AD brain pathogenesis is unknown. We show that ABCA7 is highly expressed in microglia and when monocytes are differentiated into macrophages. We hypothesized that ABCA7 plays a protective role in the brain …that is related to phagocytic clearance of amyloid-β. We isolated microglia and macrophages from Abca7–/– and wild type mice and tested them for their capacity to phagocytose amyloid-β oligomers. We found that the phagocytic clearance of amyloid-β was substantially reduced in both microglia and macrophages from Abca7–/– mice compared to wild type mice. Consistent with these results, in vivo phagocytic clearance of amyloid-β oligomers in the hippocampus was reduced in Abca7–/– mice. Furthermore, ABCA7 transcription was upregulated in AD brains and in amyloidogenic mouse brains specifically in the hippocampus as a response to the amyloid-β pathogenic state. Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD. Show more

Keywords: ABCA7, Alzheimer’s disease, amyloid-beta, brain, microglia, mouse model, phagocytosis

DOI: 10.3233/JAD-160456

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 569-584, 2016

Authors: Liu, Siwei | Ong, Yi-Ting | Hilal, Saima | Loke, Yng Miin | Wong, Tien Y. | Chen, Christopher Li-Hsian | Cheung, Carol Y. | Zhou, Juan

Article Type: Research Article

Abstract: Both healthy and pathological aging due to Alzheimer’s disease (AD) are associated with decreased brain grey matter volume (GMV) and disrupted white matter (WM) microstructure. Thinner macular ganglion cell-inner plexiform layer (GC-IPL) measured by spectral-domain optical coherence tomography has been reported in patients with AD and mild cognitive impairment. Emerging evidence suggested a link between thinner GC-IPL and lower GMV in subjects with no dementia using region-of-interest-based approach. However, it remains unknown whether GC-IPL thickness is associated with brain WM microstructure and how such association differed between normal and cognitively impaired subjects. Here, for subjects with no cognitive impairment (NCI), …thinner GC-IPL was associated with lower WM microstructure integrity in the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tracts, anterior thalamic radiation, and cingulum regions, while it was weakly associated with lower GMV in visual cortex and cerebellum. Nevertheless, these retina-brain associations were disrupted in the presence of cognitive impairment. Correlations between GMV and GC-IPL were lost in patients with cognitive impairment but no dementia (CIND) and AD patients. GC-IPL was related to WM microstructural disruption in similar regions with decreased significance. In contrast, lower WM microstructure integrity in the fornix showed a trend of correlation with thinner GC-IPL in both CIND and AD but not NCI. Collectively, our findings suggest the possible physiological retina-brain relationship in healthy aging, which might be disrupted by disease-induced changes in patients with cognitive impairment. Longitudinal study with larger patient sample should follow to confirm the disease mechanism behind these retina-brain relationship changes. Show more

Keywords: Alzheimer disease, diffusion tensor imaging, mild cognitive impairment, optical coherence tomography, retinal ganglion cells, white matter

DOI: 10.3233/JAD-160067

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 585-595, 2016

Authors: Calderón-Garcidueñas, Lilian | Avila-Ramírez, José | Calderón-Garcidueñas, Ana | González-Heredia, Tonatiuh | Acuña-Ayala, Hilda | Chao, Chih-kai | Thompson, Charles | Ruiz-Ramos, Rubén | Cortés-González, Victor | Martínez-Martínez, Luz | García-Pérez, Mario Alberto | Reis, Jacques | Mukherjee, Partha S. | Torres-Jardón, Ricardo | Lachmann, Ingolf

Article Type: Research Article

Abstract: Exposure to fine particulate matter (PM2.5 ) and ozone (O3 ) above US EPA standards is associated with Alzheimer’s disease (AD) risk, while Mn toxicity induces parkinsonism. Mexico City Metropolitan Area (MCMA) children have pre- and postnatal sustained and high exposures to PM2.5 , O3, polycyclic aromatic hydrocarbons, and metals. Young MCMA residents exhibit frontal tau hyperphosphorylation and amyloid-β (Aβ)1 - 42 diffuse plaques, and aggregated and hyperphosphorylated α-synuclein in olfactory nerves and key brainstem nuclei. We measured total prion protein (TPrP), total tau (T-tau), tau phosphorylated at threonine 181 (P-Tau), Aβ1–42 , α-synuclein (t-α-syn and d-α-synuclein), BDNF, insulin, leptin, …and/or inflammatory mediators, in 129 normal CSF samples from MCMA and clean air controls. Aβ1–42 and BDNF concentrations were significantly lower in MCMA children versus controls (p  = 0.005 and 0.02, respectively). TPrP increased with cumulative PM2.5 up to 5 μg/m3 and then decreased, regardless of cumulative value or age (R2  = 0.56). TPrP strongly correlated with T-Tau and P-Tau, while d-α-synuclein showed a significant correlation with TNFα, IL10, and IL6 in MCMA children. Total synuclein showed an increment in childhood years related to cumulated PM2.5, followed by a decrease after age 12 years (R2  = 0.47), while d-α-synuclein exhibited a tendency to increase with cumulated PM2.5 (R2  = 0.30). CSF Aβ1–42 , BDNF, α-synuclein, and TPrP changes are evolving in young MCMA urbanites historically showing underperformance in cognitive processes, odor identification deficits, downregulation of frontal cellular PrP, and neuropathological AD and PD hallmarks. Neuroprotection of young MCMA residents ought to be a public health priority. Show more

Keywords: Air pollution, Alzheimer’s disease, amyloid-β1–42, α-synuclein, BDNF, children, cerebrospinal fluid, insulin, leptin, Mexico City, prion cellular protein, PM2.5, Parkinson

DOI: 10.3233/JAD-160472

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 597-613, 2016

Authors: Brown, Eric E. | Iwata, Yusuke | Chung, Jun Ku | Gerretsen, Philip | Graff-Guerrero, Ariel

Article Type: Research Article

Abstract: A lifetime history of major depressive disorder (MDD) increases the risk of developing Alzheimer’s disease, of which neurofibrillary tangles due to abnormal tau proteins are a hallmark. We systematically reviewed the literature on tau in MDD and identified 49 relevant articles spanning a number of modalities, including cerebrospinal fluid (CSF) analysis, positron emission tomography, and clinicopathological correlation. We compared CSF total and phosphorylated tau proteins in MDD and controls using a meta-analytic approach. We found no difference in total or phosphorylated tau in MDD. We also found no difference in a comparison of a subgroup excluding studies with significant age …differences. Positron emission tomography studies lacked specificity. Clinicopathological studies failed to associate neurofibrillary tangles with MDD. The available data on tau in MDD is limited. The involvement of tau in a subset of MDD cannot be ruled out and requires prospective exploration. Show more

Keywords: Alzheimer’s disease, depression, depressive disorder, tau proteins

DOI: 10.3233/JAD-160401

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 615-633, 2016

Authors: Matsunaga, Shinji | Kishi, Taro | Iwata, Nakao

Article Type: Research Article

Abstract: Background: Previous clinical studies found that yokukansan has a therapeutic effect on behavioral and psychological symptoms of dementia (BPSD) in dementia patients. Objective: To perform an updated meta-analysis of randomized controlled trials (RCTs) testing yokukansan for patients with BPSD. Methods: Primary efficacy and safety endpoints were BPSD total scores and all-cause discontinuation, respectively. Secondary outcomes were BPSD subscales, cognitive function scores [Mini-mental state examination (MMSE)], activities of daily living (ADL) scores, discontinuation due to adverse events (AEs), and incidences of AEs. Results: Five RCTs with 381 patients with BPSD were included. Compared with …controls [placebo+usual care (UC)], yokukansan significantly decreased BPSD total scores [standardized mean difference (SMD) = –0.32, 95% confidence interval (CI) = –0.53 to –0.11, p  = 0.003, I 2  = 0%, N = 5 studies, n  = 361]. Yokukansan was more efficacious in reducing BPSD subscale scores (delusions: SMD = –0.51, 95% CI = –0.98 to –0.04, hallucinations: SMD = –0.54, 95% CI = –0.96 to –0.12, agitation/aggression: SMD = –0.37, 95% CI = –0.60 to –0.15) than placebo+UC. However, yokukansan was not superior to placebo+UC for BPSD total as well as any subscales scores only in Alzheimer’s disease patients. Compared with UC, yokukansan treatment improved ADL scores (SMD = –0.32, 95% CI = –0.62 to –0.01). MMSE scores did not differ between the yokukansan and placebo+UC treatment groups. No significant differences were found in all-cause discontinuation, discontinuation due to AEs, and incidences of AEs between yokukansan and placebo+UC treatments. Conclusions: Our results suggest that yokukansan is beneficial for the treatment of patients with BPSD and is well-tolerated; it was not beneficial for BPSD total and any subscale scores only in Alzheimer’s disease patients. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, dementia, meta-analysis, yokukansan

DOI: 10.3233/JAD-160418

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 635-643, 2016

Authors: Ordoñez-Gutierrez, Lara | Fernandez-Perez, Ivan | Herrera, Jose Luis | Anton, Marta | Benito-Cuesta, Irene | Wandosell, Francisco

Article Type: Research Article

Abstract: Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer’s disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the …AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach. Show more

Keywords: AβPP/PS1, AD mouse models, aging, Alzheimer’s disease, amyloid-β, autophagy, cerebellum, glial, sex differences, transgenic mice

DOI: 10.3233/JAD-160572

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 645-656, 2016

Authors: Struhal, Walter | Mahringer, Christoph | Lahrmann, Heinz | Mörtl, Christoph | Buhl, Peter | Huemer, Mario | Ransmayr, Gerhard

Article Type: Research Article

Abstract: Recent data suggest autonomic dysfunction in patients suffering dementia. This study evaluated autonomic modulation in dementia patients with and without autonomic involvement, employing ECG spectral analysis in the time-frequency domain (wavelet transform) in supine resting and head-up tilt (HUT) position. Thirty-six patients were prospectively evaluated at the Department of Neurology and Psychiatry, General Hospital of the City of Linz, between 2009 and 2014. A standard cardiovascular autonomic test series (Ewing battery) was performed to screen for autonomic dysfunction. The Ewing battery diagnoses were used as reference standard and compared to the diagnostic results obtained by spectral analysis (time-frequency domain) of …ECG recordings. Based on the Ewing battery results, 14 patients suffered autonomic dysfunction, while 22 did not. Time frequency domain was accessed by using the continuous wavelet transformation (CWT) with an analytical Morlet mother wavelet in supine resting and HUT position. Within each cohort the modification of spectral components from supine resting to HUT was analyzed reflecting the autonomic modulation. For patients without autonomic dysfunction, a significant increase of autonomic modulation was detected by wavelet transformed ECG recordings (8%, p  < 0.05; low frequency content) during HUT compared to supine resting. There was no significant modulation between HUT and supine resting in patients suffering autonomic dysfunction. In dementia patients suffering autonomic dysfunction, CWT identified blunted autonomic regulation only by analysis of ECG recordings without the need to assess other biosignals or tests depending on the patient’s cooperation. Further studies are needed to evaluate whether CWT is a suitable method to support the standard Ewing battery in demented patients. Show more

Keywords: Alzheimer’s disease, autonomic nervous system, continuous wavelet transformation, frontotemporal dementia, spectral analysis

DOI: 10.3233/JAD-160084

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 657-667, 2016

Authors: Beckelman, Brenna C. | Day, Stephen | Zhou, Xueyan | Donohue, Maggie | Gouras, Gunnar K. | Klann, Eric | Keene, C. Dirk | Ma, Tao

Article Type: Research Article

Abstract: Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer’s disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in …AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets. Show more

Keywords: Alzheimer’s disease, elongation factor, long-term potentiation, mTOR, protein synthesis, synaptic plasticity

DOI: 10.3233/JAD-160036

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 669-678, 2016

Authors: Yu, Qing | Fang, Du | Swerdlow, Russell Howard | Yu, Haiyang | Chen, John Xi | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Mitochondrial dysfunction and axonal degeneration are early pathological features of Alzheimer’s disease (AD)-affected brains. The underlying mechanisms and strategies to rescue it have not been well elucidated. Here, we evaluated axonal mitochondrial transport and function in AD subject-derived mitochondria. We analyzed mitochondrial transport and kinetics in human trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells whose mitochondria were derived from platelets of patients with sporadic AD and compared these AD cybrid cell lines with cybrid cell lines whose mitochondria were derived from age-matched, cognitively normal subjects. Human AD cybrid cell lines, when induced to differentiate, developed stunted projections. Mitochondrial transport and function …within neuronal processes/axons was altered in AD-derived mitochondria. Antioxidants reversed deficits in axonal mitochondrial transport and function. These findings suggest that antioxidants may be able to mitigate the consequences of AD-associated mitochondrial dysfunction. The present study provides evidence of the cause/effect of AD specific mitochondrial defects, which significantly enhances our understanding of the AD pathogenesis and exploring the effective therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, antioxidants, cybrid cells, mitochondrial dysfunction, mitochondrial transport

DOI: 10.3233/JAD-160532

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 679-690, 2016

Authors: Klafki, Hans-W. | Hafermann, Henning | Bauer, Chris | Haussmann, Ute | Kraus, Inga | Schuchhardt, Johannes | Muck, Stephan | Scherbaum, Norbert | Wiltfang, Jens

Article Type: Research Article

Abstract: A comprehensive assay validation campaign of a commercially available chemiluminescence multiplex immunoassay for the simultaneous measurement of the amyloid-β peptides Aβ38 , Aβ40 , and Aβ42 in human cerebrospinal fluid (CSF) is presented. The assay quality parameters we addressed included impact of sample dilution, parallelism, lower limits of detection, lower limits of quantification, intra- and inter-assay repeatability, analytical spike recoveries, and between laboratory reproducibility of the measurements. The assay performed well in our hands and fulfilled a number of predefined acceptance criteria. The CSF levels of Aβ40 and Aβ42 determined in a clinical cohort (n  = 203) were …statistically significantly correlated with available ELISA data of Aβ1–40 (n  = 158) and Aβ1–42 (n  = 179) from a different laboratory. However, Bland-Altman method comparison indicated systematic differences between the assays. The data presented here furthermore indicate that the CSF concentration of Aβ40 can surrogate total CSF Aβ and support the hypothesis that the Aβ42 /Aβ40 ratio outperforms CSF Aβ42 alone as a biomarker for Alzheimer’s disease due to a normalization to total Aβ levels. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, assay validation, biomarker, cerebrospinal fluid, multiplex immunoassay

DOI: 10.3233/JAD-160398

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 691-705, 2016

Authors: Hakobyan, Svetlana | Harding, Katharine | Aiyaz, Mohammed | Hye, Abdul | Dobson, Richard | Baird, Alison | Liu, Benjamine | Harris, Claire Louise | Lovestone, Simon | Morgan, Bryan Paul

Article Type: Research Article

Abstract: There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. …Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p  < 10- 5 ). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification. Show more

Keywords: Alzheimer’s disease, biomarker, complement, inflammation

DOI: 10.3233/JAD-160420

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 707-716, 2016

Authors: Cioffi, Sara M.G. | Galimberti, Daniela | Barocco, Federica | Spallazzi, Marco | Fenoglio, Chiara | Serpente, Maria | Arcaro, Marina | Gardini, Simona | Scarpini, Elio | Caffarra, Paolo

Article Type: Research Article

Abstract: Mutations in progranulin gene (GRN ) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence …of a novel mutation [g.9543delA (IVS3-2delA)] in a predicted splicing site of GRN . Her progranulin plasma levels were under the reference threshold, as in her sister, thus supporting the causative role of the new variant. The same genetic mutation was confirmed by sequencing in her sister. Results described enlarge current knowledge on genetic causes of the disease and clinical characteristics of carriers. Show more

Keywords: Deletion, frontotemporal dementia, haploinsufficiency, mutation, non-fluent variant primary progressive aphasia, progranulin (GRN), splicing

DOI: 10.3233/JAD-160185

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 717-721, 2016

Authors: Blockx, Ines | Einstein, Steve | Guns, Pieter-Jan | Van Audekerke, Johan | Guglielmetti, Caroline | Zago, Wagner | Roose, Dimitri | Verhoye, Marleen | Van der Linden, Annemie | Bard, Frederique

Article Type: Research Article

Abstract: Background: Amyloid-related imaging abnormalities (ARIA) have been reported with some anti-amyloid-β (Aβ) immunotherapy trials. They are detected with magnetic resonance imaging (MRI) and thought to represent transient accumulation of fluid/edema (ARIA-E) or microhemorrhages (ARIA-H). Although the clinical significance and pathophysiology are unknown, it has been proposed that anti-Aβimmunotherapy may affect blood-brain barrier (BBB) integrity. Objective: To examine vascular integrity in aged (12–16 months) PDAPP and wild type mice (WT), we performed a series of longitudinal in vivo MRI studies. Methods: Mice were treated on a weekly basis using anti-Aβimmunotherapy (3D6) and follow up was …done longitudinally from 1–12 weeks after treatment. BBB-integrity was assessed using both visual assessment of T1 -weighted scans and repeated T1 mapping in combination with gadolinium (Gd-DOTA). Results: A subset of 3D6 treated PDAPP mice displayed numerous BBB disruptions, whereas WT and saline-treated PDAPP mice showed intact BBB integrity under the conditions tested. In addition, the contrast induced decrease in T1 value was observed in the meningeal and midline area. BBB disruption events occurred early during treatment (between 1 and 5 weeks), were transient, and resolved quickly. Finally, BBB-leakages associated with microhemorrhages were confirmed by Perls’Prussian blue histopathological analysis. Conclusion: Our preclinical findings support the hypothesis that 3D6 leads to transient leakage from amyloid-positive vessels. The current study has provided valuable insights on the time course of vascular alterations during immunization treatment and supports further research in relation to the nature of ARIA and the utility of in vivo repeated T1 MRI as a translational tool. Show more

Keywords: Alzheimer’s disease, amyloid-related imaging abnormalities, blood-brain barrier, immunotherapy, magnetic resonance imaging, neuroimaging, transgenic mouse model

DOI: 10.3233/JAD-160023

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 723-735, 2016

Authors: Luccarini, Ilaria | Pantano, Daniela | Nardiello, Pamela | Cavone, Leonardo | Lapucci, Andrea | Miceli, Caterina | Nediani, Chiara | Berti, Andrea | Stefani, Massimo | Casamenti, Fiorella

Article Type: Research Article

Abstract: Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer’s disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 months) and intermediate (6 months) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms. Here we found that 8-week OLE treatment (50 mg/kg of diet) to 6-month-old TgCRND8 …mice rescued to control values PARP1 activation and the levels of its product, PAR. In N2a neuroblastoma cells, PARP1 activation and PAR formation upon exposure to N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) were abolished by pretreatment for 24 h with either OLE (100μM) or PARP inhibitors. A significant reduction of the NAD+ content, compared to controls, was found in N2a cells exposed to MNNG (100μM) for 90 min; the latter was slightly attenuated by cell treatment for 24 h with PJ-34 or with OLE. In vitro and in vivo , the OLE-induced reduction of PARP1 activation was paralleled by the overexpression of Sirtuin1 (SIRT1), and, in vivo , by a decrease of NF-κ B and the pro-apoptotic marker p53. In N2a cells, we also found that OLE potentiates the MNNG-induced increase of Beclin1 levels. In conclusion, our data show that OLE treatment counteracts neuronal damage through modulation of the PARP1-SIRT1 interplay. Show more

Keywords: Alzheimer’s disease, animal model of Aβ deposition, olive oil polyphenols, PAR polymers

DOI: 10.3233/JAD-160471

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 737-750, 2016

Authors: Pérez-Grijalba, Virginia | Fandos, Noelia | Canudas, Jesús | Insua, Daniel | Casabona, Diego | Lacosta, Ana M. | Montañés, María | Pesini, Pedro | Sarasa, Manuel

Article Type: Research Article

Abstract: Recent advances in neuroimaging and cerebrospinal fluid (CSF) biomarker assays have provided evidence of a long preclinical stage of Alzheimer’s disease (AD). This period is being increasingly targeted for secondary prevention trials of new therapies. In this context, the interest of a noninvasive, cost-effective amyloid-β (Aβ) blood-based test does not need to be overstated. Nevertheless, a thorough validation of these bioanalytical methods should be performed as a prerequisite for confident interpretation of clinical results. The aim of this study was to validate ELISA sandwich colorimetric ABtest40 and ABtest42 for the quantification of Aβ40 and Aβ42 in human plasma. …The validation parameters assessed included precision, accuracy, sensitivity, specificity, recovery, and dilution linearity. ABtest40 and ABtest42 proved to be specific for their target peptide using Aβ peptides with sequence similar to the target. Mean relative error in the quantification was found to be below 7.5% for both assays, with high intra-assay, inter-assay, and inter-batch precision (CV <9.0% on average). Sensitivity was assessed by determination of the limit of quantification fulfilling precision and accuracy criteria; it was established at 7.60 pg/ml and 3.60 pg/ml for ABtest40 and ABtest42, respectively. Plasma dilution linearity was demonstrated in PBS; however, dilution in a proprietary formulated buffer significantly increased the recovery of both Aβ40 and Aβ42 masked by matrix interactions, allowing a more comprehensive assessment of the free and total peptide levels in the plasma. In conclusion, both assays were successfully validated as tools for the quantification Aβ40 and Aβ42 in plasma. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, biomarker, immunoassay validation, plasma

DOI: 10.3233/JAD-160325

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 751-762, 2016

Authors: Morozov, Alexey V. | Kulikova, Alexandra A. | Astakhova, Tatiana M. | Mitkevich, Vladimir A. | Burnysheva, Ksenia M. | Adzhubei, Alexei A. | Erokhov, Pavel A. | Evgen’ev, Michail B. | Sharova, Natalia P. | Karpov, Vadim L. | Makarov, Alexander A.

Article Type: Research Article

Abstract: Accumulation of amyloid-β (Aβ) in neurons accompanies Alzheimer’s disease progression. In the cytoplasm Aβ influences activity of proteasomes, the multisubunit protein complexes that hydrolyze the majority of intracellular proteins. However, the manner in which Aβ affects the proteolytic activity of proteasomes has not been established. In this study the effect of Aβ42 and Aβ42 with isomerized Asp7 on activity of different forms of proteasomes has been analyzed. It has been shown that Aβ peptides efficiently reduce activity of the 20S proteasomes, but increase activity of the 20S proteasomes capped with the 19S and/or 11S regulators. Modulation of proteasome …activity is mainly determined by the C-terminal segment of Aβ (amino acids 17-42). This study demonstrated an important role of proteasome regulators in the interplay between Aβ and the proteasomes. Show more

Keywords: Keywords: Alzheimer’s disease, amyloid-β, 20S proteasome, 19S regulator particle, 11S regulator

DOI: 10.3233/JAD-160491

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 763-776, 2016

Authors: Lozano, Andres M. | Fosdick, Lisa | Chakravarty, M. Mallar | Leoutsakos, Jeannie-Marie | Munro, Cynthia | Oh, Esther | Drake, Kristen E. | Lyman, Christopher H. | Rosenberg, Paul B. | Anderson, William S. | Tang-Wai, David F. | Pendergrass, Jo Cara | Salloway, Stephen | Asaad, Wael F. | Ponce, Francisco A. | Burke, Anna | Sabbagh, Marwan | Wolk, David A. | Baltuch, Gordon | Okun, Michael S. | Foote, Kelly D. | McAndrews, Mary Pat | Giacobbe, Peter | Targum, Steven D. | Lyketsos, Constantine G. | Smith, Gwenn S.

Article Type: Research Article

Abstract: Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer’s disease (AD). Methods: We evaluated active “on” versus sham “off” bilateral DBS directed at the fornix-a major fiber bundle in the brain’s memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. Results: Surgery and electrical …stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the “on” versus “off” stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n  = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n  = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism. Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation. Show more

Keywords: Keywords: Alzheimer’s disease, dementia, deep brain stimulation, fornix

DOI: 10.3233/JAD-160017

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 777-787, 2016

Authors: Fried, Itzhak

Article Type: Article Commentary

Abstract: Deep brain stimulation has been successfully used in treatment of motor symptoms of Parkinson’s disease and other movement disorders. In a recent multi-center prospectively randomized study, deep brain stimulation of the fornix was administered in order to ameliorate the cognitive symptoms and clinical course of Alzheimer’s disease (AD). The study points to the possibility of modest slowing of the cognitive decline in AD in a subset of patients older than 65, while at the same time highlights the risk of stimulation in exacerbation of this decline in younger patients. The logic of conducting large clinical trials in the face of …limited scientific understanding of the pathophysiology of AD and response of affected brain regions to electrical stimulation, is discussed with emphasis on the need to conduct: (i) animal studies in AD models, using precise focused stimulation; (ii) studies in patients who are implanted with depth electrodes for established clinical reasons (i.e., patients with epilepsy or movement disorders); and (iii) smaller adaptive studies in AD patients with systematic alterations of therapeutic parameters such as stimulation protocol. Show more

Keywords: Alzheimer’s disease, dementia, deep brain stimulation, fornix, hippocampus, entorhinal area

DOI: 10.3233/JAD-160719

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 789-791, 2016

Authors: Curiel, Rosie E. | Crocco, Elizabeth | Rosado, Marian | Duara, Ranjan | Greig, Maria T. | Raffo, Arlene | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: Semantic memory interference has been found to be a predictive cognitive marker of incipient AD. This is relevant given that developing assessment paradigms to identify subtle cognitive and functional deficits is a priority in preclinical Alzheimer’s disease research. Objective: To examine the utility of a novel computerized paired associate test in distinguishing between mild cognitive impairment (MCI) and cognitively normal (CN) groups of older adults residing in the community. Methods: Participants that were CN (n  = 64) or MCI (n  = 34) were administered the Miami Test of Semantic Interference and Learning (MITSI-L). This novel instrument …is a brief, computerized paired associate test that measured the strength of memory binding of semantically related word pairs and introduced a proactive semantic interference condition which required participants to make different associations between semantically similar targets. A series of ANOVAs explored differences on MITSI-L performance. Logistic regression and receiver operator curves (ROC) analyses were employed to further determine discriminative validity. Results: MCI participants had lower scores on all indices relative to CN elders. A composite of two subscores correctly classified 85.3% of MCI and 84.4% of CN participants. Area under the ROC was higher relative to the MMSE, immediate memory for passages, and several subtests of a sensitive memory measure, the LASSI-L. Conclusions: The MITSI-L is a computerized test that can successfully differentiate MCI from CN participants. Area under the ROC curve exceeded that of global mental status and other memory measures. The effectiveness of the MITSI-L in detecting MCI, and its brief administration and portability render it worthy of further research. Show more

Keywords: Alzheimer’s disease, computerized tests, memory, mild cognitive impairment, MITSI-L

DOI: 10.3233/JAD-160370

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 793-799, 2016

Authors: Gomm, Willy | von Holt, Klaus | Thomé, Friederike | Broich, Karl | Maier, Wolfgang | Weckbecker, Klaus | Fink, Anne | Doblhammer, Gabriele | Haenisch, Britta

Article Type: Research Article

Abstract: Background: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing. Objective: To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set. Methods: Using longitudinal German public health insurance data …from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy. Results: The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13–1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed. Conclusion: The restricted use of BDZRs may contribute to dementia prevention in the elderly. Show more

Keywords: Benzodiazepines, dementia, elderly, risk factor, z-substances

DOI: 10.3233/JAD-151006

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 801-808, 2016

Authors: Khmeleva, Svetlana A. | Radko, Sergey P. | Kozin, Sergey A. | Kiseleva, Yana Y. | Mezentsev, Yuri V. | Mitkevich, Vladimir A. | Kurbatov, Leonid K. | Ivanov, Alexis S. | Makarov, Alexander A.

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ) plays a central role in Alzheimer’s disease (AD) pathogenesis. Besides extracellular Aβ, intraneuronal Aβ (iAβ) has been suggested to contribute to AD onset and development. Based on reported in vitro Aβ-DNA interactions and nuclear localization of iAβ, the interference of iAβ with the normal DNA expression has recently been proposed as a plausible pathway by which Aβ can exert neurotoxicity. Employing the sedimentation assay, thioflavin T fluorescence, and dynamic light scattering we have studied effects of zinc ions on binding of RNA and single- and double-stranded DNA molecules to Aβ42 aggregates. It has been found …that zinc ions significantly enhance the binding of RNA and DNA molecules to pre-formed β-sheet rich Aβ42 aggregates. Another type of Aβ42 aggregates, the zinc-induced amorphous aggregates, was demonstrated to also bind all types of nucleic acids tested. To evaluate the role of the Aβ metal-binding domain’s histidine residues in Aβ-nucleic acid interactions mediated by zinc, Aβ16 mutants with substitutions H6R and H6A-H13A and rat Aβ16 lacking histidine residue 13 were used. The zinc-induced interaction of Aβ16 with DNA was shown to critically depend on histidine residues 6 and 13. However, the inclusion of H6R mutation in Aβ42 peptide did not affect DNA binding to Aβ42 aggregates. Since oxidative and/or nitrosative stresses implicated in AD pathogenesis are known to release zinc ions from metallothioneins in cytoplasm and cell nuclei, our findings suggest that intracellular zinc can be an important player in iAβ-nucleic acid interactions. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, DNA, histidine residues, RNA, zinc

DOI: 10.3233/JAD-160415

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 809-819, 2016

Authors: Selivanova, Olga M. | Surin, Alexey K. | Marchenkov, Victor V. | Dzhus, Ulyana F. | Grigorashvili, Elizaveta I. | Suvorina, Mariya Yu. | Glyakina, Anna V. | Dovidchenko, Nikita V. | Galzitskaya, Oxana V.

Article Type: Research Article

Abstract: It has been demonstrated using Aβ40 and Aβ42 recombinant and synthetic peptides that their fibrils are formed of complete oligomer ring structures. Such ring structures have a diameter of about 8-9 nm, an oligomer height of about 2– 4 nm, and an internal diameter of the ring of about 3-4 nm. Oligomers associate in a fibril in such a way that they interact with each other, overlapping slightly. There are differences in the packing of oligomers in fibrils of recombinant and synthetic Aβ peptides. The principal difference is in the degree of orderliness of ring-like oligomers that leads to generation of …morphologically different fibrils. Most ordered association of ring-like structured oligomers is observed for a recombinant Aβ40 peptide. Less ordered fibrils are observed with the synthetic Aβ42 peptide. Fragments of fibrils the most protected from the action of proteases have been determined by tandem mass spectrometry. It was shown that unlike Aβ40 , fibrils of Aβ42 are more protected, showing less ordered organization compared to that of Aβ40 fibrils. Thus, the mass spectrometry data agree with the electron microscopy data and structural models presented here. Show more

Keywords: Aβ42 and Aβ40 peptides, Alzheimer’s disease, amyloid fibrils, polymorphism, ring-like oligomers

DOI: 10.3233/JAD-160405

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 821-830, 2016

Authors: Zimova, Ivana | Brezovakova, Veronika | Hromadka, Tomas | Weisova, Petronela | Cubinkova, Veronika | Valachova, Bernadeta | Filipcik, Peter | Jadhav, Santosh | Smolek, Tomas | Novak, Michal | Zilka, Norbert

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151–391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting …of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy. Show more

Keywords: Alzheimer’s disease, neurofibrillary degeneration, tauopathies, transgenic mouse, truncated tau protein

DOI: 10.3233/JAD-160347

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 831-843, 2016

Authors: Cestari, José Augusto Ferrari | Fabri, Gisele Maria Campos | Kalil, Jorge | Nitrini, Ricardo | Jacob-Filho, Wilson | Tesseroli de Siqueira, José Tadeu | Siqueira, Silvia Regina D.T.

Article Type: Correction

DOI: 10.3233/JAD-169006

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 845-845, 2016

Article Type: Other

DOI: 10.3233/JAD-160728

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 847-852, 2016