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