Journal of Alzheimer's Disease - Volume 55, issue 1

Authors: Dal-Pan, Alexandre | Dudonné, Stéphanie | Bourassa, Philippe | Bourdoulous, Morgane | Tremblay, Cyntia | Desjardins, Yves | Calon, Frédéric | on behalf of the Neurophenols consortium

Article Type: Research Article

Abstract: No effective preventive treatment is available for age-related cognitive decline and Alzheimer’s disease (AD). Epidemiological studies indicate that a diet rich in fruit is associated with cognitive improvement. It was thus proposed that high polyphenol concentrations found in berries can prevent cognitive impairment associated with aging and AD. Therefore, the Neurophenols project aimed at investigating the effects of a polyphenolic extract from blueberries and grapes (PEBG) in the triple-transgenic (3xTg-AD) mouse model of AD, which develops AD neuropathological markers, including amyloid-β plaques and neurofibrillary tangles, leading to memory deficits. In this study, 12-month-old 3xTg-AD and NonTg mice were fed a …diet supplemented with standardized PEBG (500 or 2500 mg/kg) for 4 months (n  = 15–20/group). A cognitive evaluation with the novel object recognition test was performed at 15 months of age and mice were sacrificed at 16 months of age. We observed that PEBG supplementation with doses of 500 or 2500 mg/kg prevented the decrease in novel object recognition observed in both 15-month-old 3xTg-AD mice and NonTg mice fed a control diet. Although PEBG treatment did not reduce Aβ and tau pathologies, it prevented the decrease in mature BDNF observed in 16-month-old 3xTg-AD mice. Finally, plasma concentrations of phenolic metabolites, such as dihydroxyphenyl valerolactone, a microbial metabolite of epicatechin, positively correlated with memory performances in supplemented mice. The improvement in object recognition observed in 3xTg-AD mice after PEBG administration supports the consumption of polyphenols-rich extracts to prevent memory impairment associated with age-related disease, without significant effects on classical AD neuropathology. Show more

Keywords: 3xTg-AD, age-related cognitive decline, Alzheimer’s disease, polyphenols

DOI: 10.3233/JAD-160281

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 115-135, 2017

Authors: Kim, Hang-Rai | Park, Young Ho | Jang, Jae-Won | Park, So Young | Wang, Min Jeong | Baek, Min Jae | Kim, Beom Joon | Ahn, Soyeon | Kim, SangYun

Article Type: Research Article

Abstract: Background: Although medial temporal atrophy (MTA) is a useful imaging marker of the progression to dementia in mild cognitive impairment (MCI), substantial numbers of MCI patients without MTA still progress to dementia. Objective: We investigated whether visual ratings of posterior atrophy (PA) on magnetic resonance imaging show independent predictive value for the progression to dementia in MCI patients. Methods: This was a retrospective cohort study of elderly patients who visited Seoul National University Bundang Hospital between 2004 and 2012. A total of 148 patients who were initially diagnosed with MCI were followed for up to …3 years (median 22 months) to determine whether they progressed to dementia. We used 4-point and 5-point visual rating scales to assess PA and MTA, respectively. PA and MTA scores were dichotomized into normal (no atrophy) or abnormal (atrophy) in each patient. We performed a Cox regression analysis to examine the hazard ratios (HRs) of PA and MTA for the progression to dementia with adjustment for age, APOE ɛ 4 allele status, and baseline Mini-Mental State Examination score. Results: Among the study population, 47 patients progressed to dementia. Visual assessment of the MRI scans revealed that 67 patients (45.3%) showed PA, whereas 85 patients (57.3%) showed MTA. The HRs with 95% confidence intervals for PA and MTA were 2.516 (1.244–5.091) and 4.238 (1.680–10.687), respectively. The predictive values of visually assessed PA and MTA remained significant, independent of the covariates. Conclusion: Visual assessment of PA has independent predictive value for progression to dementia in MCI patients. Show more

Keywords: Atrophy, biomarker, disease progression, mild cognitive impairment

DOI: 10.3233/JAD-160339

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 137-146, 2017

Authors: Gureviciene, Irina | Gurevicius, Kestutis | Mugantseva, Ekaterina | Kislin, Mikhail | Khiroug, Leonard | Tanila, Heikki

Article Type: Research Article

Abstract: Amyloid plaques, although inducing damage to the immediately surrounding neuropil, have been proposed to provide a relatively innocuous way to deposit toxic soluble amyloid-β (Aβ) species. Here we address this hypothesis by exploring spread and absorption of fluorescent Aβ to pre-existing amyloid plaques after local application in wild-type mice versus APP/PS1 transgenic mice with amyloid plaques. Local intracortical or intracerebroventricular injection of fluorescently-labeled Aβ in APP/PS1 mice with a high plaque density resulted in preferential accumulation of the peptide in amyloid plaques in both conventional postmortem histology and in live imaging using two-photon microscopy. These findings support the contention that …amyloid plaques may act as buffers to protect neurons from the toxic effects of momentary high concentrations of soluble Aβ oligomers. Show more

Keywords: Alzheimer’s disease, amyloid-β, in vivo imaging, multiphoton, transgenic

DOI: 10.3233/JAD-160453

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 147-157, 2017

Authors: Lewczuk, Piotr | Lelental, Natalia | Lachmann, Ingolf | Holzer, Max | Flach, Katharina | Brandner, Sebastian | Engelborghs, Sebastiaan | Teunissen, Charlotte E. | Zetterberg, Henrik | Molinuevo, José Luis | Mroczko, Barbara | Blennow, Kaj | Popp, Julius | Parnetti, Lucilla | Chiasserini, Davide | Perret-Liaudet, Armand | Spitzer, Philipp | Maler, Juan Manuel | Kornhuber, Johannes

Article Type: Research Article

Abstract: Background: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF). Objective: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF. Methods: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method. Results: The 1G2 antibody shows decreasing reactivity to tau peptides containing …phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6–15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% – 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer’s disease in stage of mild cognitive impairment or dementia (AD/MCI, n  = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n  = 42, 62.1±9.3 pg/mL, p  < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively. Conclusion: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF. Show more

Keywords: Biomarkers, cerebrospinal fluid, phosphorylation, tau

DOI: 10.3233/JAD-160448

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 159-170, 2017

Authors: Domínguez-Prieto, Marta | Velasco, Ana | Vega, Lourdes | Tabernero, Arantxa | Medina, José M.

Article Type: Research Article

Abstract: Amyloid-β (Aβ), Aβ40 , Aβ42 , and, recently, Aβ25-35 have been directly implicated in the pathogenesis of Alzheimer’s disease. We have studied the effects of Aβ on neuronal death, reactive oxygen species (ROS) production, and synaptic assembling in neurons in primary culture. Aβ25-35 , Aβ40 , and Aβ42 significantly decreased neuronal viability, although Aβ25-35 showed a higher effect. Aβ25-35 showed a more penetrating ability to reach mitochondria while Aβ40 did not enter the neuronal cytosol and Aβ42 was scarcely internalized. We did not observe a direct correlation between ROS production and cell death because …both Aβ40 and Aβ42 decreased neuronal viability but Aβ40 did not change ROS production. Rather, ROS production seems to correlate with the penetrating ability of each Aβ. No significant differences were found between Aβ40 and Aβ42 regarding the extent of the deleterious effects of both peptides on neuronal viability or synaptophysin expression. However, Aβ40 elicited a clear delocalization of PSD-95 and synaptotagmin from prospective synapsis to the neuronal soma, suggesting the occurrence of a crucial effect of Aβ40 on synaptic disassembling. The formation of Aβ40 - or Aβ42 -serum albumin complexes avoided the effects of these peptides on neuronal viability, synaptophysin expression, and PSD-95/synaptotagmin disarrangement suggesting that sequestration of Aβ by albumin prevents deleterious effects of these peptides. We can conclude that Aβ borne by albumin can be safely transported through body fluids, a fact that may be compulsory for Aβ disposal by peripheral tissues. Show more

Keywords: Alzheimer’s disease, Aβ disposal, amyloid-beta, PSD-95, serum albumin, synaptophysin, synaptotagmin

DOI: 10.3233/JAD-160346

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 171-182, 2017

Authors: Cerami, Chiara | Dodich, Alessandra | Greco, Lucia | Iannaccone, Sandro | Magnani, Giuseppe | Marcone, Alessandra | Pelagallo, Elisabetta | Santangelo, Roberto | Cappa, Stefano F. | Perani, Daniela

Article Type: Research Article

Abstract: Background and Objective: Primary progressive aphasia (PPA) is a clinical syndrome due to different neurodegenerative conditions in which an accurate early diagnosis needs to be supported by a reliable diagnostic tool at the individual level. In this study, we investigated in PPA the FDG-PET brain metabolic patterns at the single-subject level, in order to assess the case-to-case variability and its relationship with clinical-neuropsychological findings. Material and Methods: 55 patients (i.e., 11 semantic variant/sv-PPA, 19 non fluent variant/nfv-PPA, 17 logopenic variant/lv-PPA, 3 slowly progressive anarthria/SPA, and 5 mixed PPA/m-PPA) were included. Clinical-neuropsychological information and FDG-PET data were acquired …at baseline. A follow-up of 27.4±12.55 months evaluated the clinical progression. Brain metabolism was analyzed using an optimized and validated voxel-based SPM method at the single-subject level. Results: FDG-PET voxel-wise metabolic assessment revealed specific metabolic signatures characterizing each PPA variant at the individual level, reflecting the underlying neurodegeneration in language networks. Notably, additional dysfunctional patterns predicted clinical progression to specific dementia conditions. In the case of nfv-PPA, a metabolic pattern characterized by involvement of parietal, subcortical and brainstem structures predicted progression to a corticobasal degeneration syndrome or to progressive supranuclear palsy. lv-PPA and sv-PPA cases who progressed to Alzheimer’s disease and frontotemporal dementia at the follow-up presented with extended bilateral patterns at baseline. Discussion: Our results indicate that FDG-PET voxel-wise imaging is a valid biomarker for the early differential diagnosis of PPAs and for the prediction of progression to specific dementia condition. This study supports the use of FDG-PET imaging quantitative assessment in clinical settings for a better characterization of PPA individuals and prognostic definition of possible endo-phenotypes. Show more

Keywords: FDG-PET, logopenic variant of primary progressive aphasia, non fluent variant of primary progressive aphasia, primary progressive aphasia, positron emission tomography, semantic variant of primary progressive aphasia

DOI: 10.3233/JAD-160682

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 183-197, 2017

Authors: Raha, Animesh Alexander | Henderson, James W. | Stott, Simon R.W. | Vuono, Romina | Foscarin, Simona | Friedland, Robert P. | Zaman, Shahid H. | Raha-Chowdhury, Ruma

Article Type: Research Article

Abstract: Neuroinflammation and activation of innate immunity are early events in neurodegenerative diseases including Alzheimer’s disease (AD). Recently, a rare mutation in the gene Triggering receptor expressed on myeloid cells 2 (TREM2) has been associated with a substantial increase in the risk of developing late onset AD. To uncover the molecular mechanisms underlying this association, we investigated the RNA and protein expression of TREM2 in APP/PS1 transgenic mice. Our findings suggest that TREM2 not only plays a critical role in inflammation, but is also involved in neuronal cell survival and in neurogenesis. We have shown that TREM2 is a soluble protein …transported by macrophages through ventricle walls and choroid plexus, and then enters the brain parenchyma via radial glial cells. TREM2 protein is essential for neuroplasticity and myelination. During the late stages of life, a lack of TREM2 protein may accelerate aging processes and neuronal cell loss and reduce microglial activity, ultimately leading to neuroinflammation. As inflammation plays a major role in neurodegenerative diseases, a lack of TREM2 could be a missing link between immunomodulation and neuroprotection. Show more

Keywords: Alzheimer’ disease, choroid plexus macrophages, innate immunity, immunomodulation, myelination, neurogenesis, neuroinflammation, neuroplasticity, neuroprotective, soluble TREM2

DOI: 10.3233/JAD-160663

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 199-217, 2017

Authors: Robillard, Julie M. | Feng, Tanya L.

Article Type: Research Article

Abstract: Background: As the number of older adults turning to the Internet for health information increases, so does the potential for online information to have a substantial impact on the patient-physician relationship and on their health. Inaccurate information may weaken patient-physician relationships or result in increased physician visits and health anxiety, while high quality information may allow Internet users to make better decisions about their health. Objective: To assess the quality and content of available online resources about the prevention of Alzheimer’s disease (AD). Methods: A sample of 308 articles related to the prevention of AD …was collected from the first three pages of location-independent keyword searches on Google.com between September 17–30, 2014. Content analysis was applied to articles that met criteria (n  = 298) and a quality evaluation tool was developed to generate a quality score for each of the articles (n  = 290). Results: We found that articles on the high end of the quality spectrum focused on modifiable risk factors and tended to present balanced information, while articles of low quality emphasized nutrition as a method of prevention and were more likely to be in conflict of interest. Conclusion: This study provides the first insight into the content and quality of prevention information for AD currently available online and highlights the importance of future research to better understand the impact of this information on the patient-physician relationship and health decision-making of older adults. Show more

Keywords: Alzheimer’s disease, consumer health information, Internet, prevention

DOI: 10.3233/JAD-160650

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 219-229, 2017

Authors: Rodríguez Cruz, Yamila | Strehaiano, Manon | Rodríguez Obaya, Teresita | García Rodríguez, Julío César | Maurice, Tangui

Article Type: Research Article

Abstract: Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer’s disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. …Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1–42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1–42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice. Show more

Keywords: Alzheimer’s disease, erythropoietin, intranasal formulation, learning and memory, Neuro-EPO, neuroprotection

DOI: 10.3233/JAD-160500

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 231-248, 2017

Authors: Fong, Jamie C. | Rojas, Julio C. | Bang, Jee | Legati, Andrea | Rankin, Katherine P. | Forner, Sven | Miller, Zachary A. | Karydas, Anna M. | Coppola, Giovanni | Grouse, Carrie K. | Ralph, Jeffrey | Miller, Bruce L. | Geschwind, Michael D.

Article Type: Research Article

Abstract: Patients with pathogenic truncating mutations in the prion gene (PRNP ) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first …report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history. Show more

Keywords: Amyloidosis, DNA sequencing, dysautonomia, exome, mutation, peripheral neuropathy, prion dementia

DOI: 10.3233/JAD-160300

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 249-258, 2017