Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Coebergh, Jan A.F. | McDowell, Steven | van Woerkom, Theodorus C.A.M. | Koopman, Jan P. | Mulder, Jacqueline | Bruijn, Sebastiaan F.T.M.

Article Type: Research Article

Abstract: Auditory agnosia for environmental sounds (AES) is an example of central auditory dysfunction. It is presumed to be independent of language deficits and in presence of normal hearing. We undertook a detailed neuropsychological assessment including environmental sound naming and recognition in 34 clinically mild Alzheimer’s disease (AD) patients and 29 age-matched healthy control subjects. In patients with AD, audiometry was performed to assess the impact on test performance, and in normal controls the Hearing Handicap Inventory for the Elderly – Screening Version to exclude more than mild hearing loss. We adapted a validated environmental sound battery and found near perfect …scores in controls. We found that environmental sound agnosia is common in mild AD. We found a statistically significant difference in mean pure tone audiometry in the best ear between patients with and those patients without naming deficits of 11.3 dB (p  = 0.010) and of 14.7 dB (p  = 0.000) between those with and without recognition deficits. Statistical significance remained after correcting for age, aphasia, Mini-Mental State Examination score, and working memory. Slight and moderate peripheral hearing loss increases the odds ratio of recognition deficits by 13.75 (confidence interval 2.3–81.5) compared to normal hearing patients. We did not find evidence for different forms of AES. This work suggests that an interaction between peripheral hearing loss and AD pathology produces problems with environmental sound recognition. It confirms that the relationship between hearing and dementia is complex but also suggests that interventions to prevent and treat hearing loss could have an effect on AD in its clinical expression. Show more

Keywords: Alzheimer’s disease, central auditory dysfunction, environmental sound agnosia, hearing loss

DOI: 10.3233/JAD-190431

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Furman, Ran | Ng, Sharon C.W. | Komatsu, Hiroaki | Axelsen, Paul H.

Article Type: Research Article

Abstract: Various amyloid-β (Aβ) peptides accumulate in brain in Alzheimer’s disease, and the amounts of specific peptide variants may have pathological significance. The quantitative determination of these variants is challenging because losses inevitably occur during tissue processing and analysis. This report describes the use of stable-isotope-labeled Aβ peptides as internal standards for quantitative mass spectrometric assays, and the use of cyanogen bromide (CNBr) to remove C-terminal residues beyond Met35. The removal of residues beyond Met35 reduces losses due to aggregation, and facilitates the detection of post-translationally modified Aβ peptides. Results from 8 human brain samples suggest that the tissue concentrations of …the 42-residue Aβ peptide tend to be similar in different patients. Concentrations of the 40-residue Aβ peptide are more variable, and may be greater or lesser than the 42-residue peptide. The concentration of the CNBr cleavage product closely matches the sum of the 40-residue and 42-residue peptide concentrations, indicating that these two Aβ peptides account for most of the C-terminal variants in these patients. CNBr treatment facilitated the detection of post-translational modifications such as pyroglutamyl and hexose-modified Aβ peptides. Show more

Keywords: Immunoprecipitation, internal standards, isotope labeling, post-translational modification

DOI: 10.3233/JAD-190647

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Prikhodko, Olga | Rynearson, Kevin D. | Sekhon, Travis | Mante, Mike M. | Nguyen, Phuong D. | Rissman, Robert A. | Tanzi, Rudolph E. | Wagner, Steven L.

Article Type: Research Article

Abstract: Background: In the amyloid hypothesis of Alzheimer’s disease (AD), the dysregulation of amyloid-β protein (Aβ) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aβ production have been found ineffective or having significant side effects. Objective: To test whether a γ -secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD. Methods: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points. …Results: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed. Conclusion: BPN-15606 appears efficacious when administered prior to significant pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β , BPN-15606, cognitive deficits, γ-secretase modulator, preventative therapy, PSAPP

DOI: 10.3233/JAD-190442

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Falgàs, Neus | Balasa, Mircea | Bargalló, Núria | Borrego-Écija, Sergi | Ramos-Campoy, Oscar | Fernández-Villullas, Guadalupe | Bosch, Beatriz | Olives, Jaume | Tort-Merino, Adrià | Antonell, Anna | Castellví, Magdalena | Allen, Isabel E. | Sánchez-Valle, Raquel | Lladó, Albert

Article Type: Research Article

Abstract: Background: The diagnosis of incipient symptomatic stages of early-onset dementia is challenging. The magnetic resonance imaging (MRI) is an easy-access biomarker. Objective: We aim to determine the distribution and diagnostic performance of the existing atrophy visual rating scales on MRI in initial stages of the most frequent neurodegenerative early onset dementias. Methods: We evaluated the visual atrophy scales usefulness in two hundred subjects: seventy sporadic early onset Alzheimer’s disease (AD) patients (48 amnestic and 22 non-amnestic), 14 patients with autosomal-dominant AD (ADAD), 25 sporadic frontotemporal dementia patients [11 with behavioral variant (bvFTD), nine with semantic variant …of primary progressive aphasia (svPPA), and 5 with non-fluent primary progressive aphasia (nfvPPA)], 7 with genetically determined FTD (genetic FTD), 25 mild cognitive impairment due to non-degenerative disorders, and 59 healthy controls. All had MMSE≥18, 3T-brain MRI, and biomarker-supported diagnosis. Two raters evaluated six frontal, temporal, and parietal scales. Inter-rater reliability and diagnostic performance in terms of area under the receiver-operator curves and balanced accuracy were analyzed. Results: Best scales to discriminate AD from controls were the anterior cingulate scale for amnestic and the posterior atrophy scale for sporadic non-amnestic AD and ADAD. The anterior temporal scale was the best for sporadic bvFTD and svPPA and the anterior cingulate scale was for nfvPPA. All scales performed well for the genetic FTD. However, no scale demonstrated good performance at discriminating AD from FTD or non-degenerative disorders. Conclusions: The clinicians should interpret with caution atrophy scale assessment in subjects with early-onset cognitive impairment given that none of the evaluated scales met the requirements for being a diagnostic biomarker. Show more

Keywords: Alzheimer’s disease, atrophy, frontotemporal dementia, magnetic resonance imaging

DOI: 10.3233/JAD-191167

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Faura, Júlia | Bustamante, Alejandro | Penalba, Anna | Giralt, Dolors | Simats, Alba | Martínez-Sáez, Elena | Alcolea, Daniel | Fortea, Juan | Lleó, Alberto | Teunissen, Charlotte E. | van der Flier, Wiesje M. | Ibañez, Laura | Harari, Oscar | Cruchaga, Carlos | Hernández-Guillamón, Mar | Delgado, Pilar | Montaner, Joan

Article Type: Research Article

Abstract: CCL23 is a chemokine implicated in inflammation and host defense responses. It has been recently associated with acquired brain damage and stroke outcomes. In this study, we reported the role of CCL23 in Alzheimer’s disease (AD). We evaluated the levels of CCL23 in 659 individuals: cognitively normal, mild cognitive impaired (MCI), and AD patients. Two cross-sectional (study 1, n  = 53; study 2, n  = 200) and two longitudinal (study 3, n  = 74; study 4, n  = 332) studies were analyzed separately. CCL23 levels in the blood and/or cerebrospinal fluid (CSF) of each study were measured by immunoassays. Globally, our results suggest a …predictive role of CCL23 protein levels both in the plasma in study 3 (hazard ratio (HR) = 2.5 (confidence interval (CI) 95% : 1.2–5.3), p  = 0.02) and in the CSF in study 4 (HR = 3.05 (CI 95% : 1.02–5), p  = 0.04) in cases of MCI that progress to AD. Moreover, we observed that the APOE ɛ 4 allele was associated with higher levels of CCL23 in study 2 (470.33 pg/mL (interquartile range (IQR): 303.33–597.76) versus 377.94 pg/mL (IQR: 267.16–529.19), p  = 0.01) (APOE genotypes were available in studies 2 and 4). Together, these findings support the role of CCL23 in neuroinflammation in the early stages of AD, suggesting that CCL23 might be a candidate blood biomarker for MCI to AD progression. Show more

Keywords: Alzheimer’s disease, biomarkers, chemokines, cognitive dysfunction, early diagnosis

DOI: 10.3233/JAD-190753

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Ono, Kenjiro | Zhao, Daisy | Wu, Qingli | Simon, James | Wang, Jun | Radu, Aurelian | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Plant-derived polyphenolic compounds possess diverse biological activities, including strong anti-oxidant, anti-inflammatory, anti-microbial, and anti-tumorigenic activities. There is a growing interest in the development of polyphenolic compounds for preventing and treating chronic and degenerative diseases, such as cardiovascular disorders, cancer, and neurological diseases including Alzheimer’s disease (AD). Two neuropathological changes of AD are the appearance of neurofibrillary tangles containing tau and extracellular amyloid deposits containing amyloid-β protein (Aβ). Our laboratory and others have found that polyphenolic preparations rich in proanthocyanidins, such as grape seed extract, are capable of attenuating cognitive deterioration and reducing brain neuropathology in animal models of AD. Oligopin …is a pine bark extract composed of low molecular weight proanthocyanidins oligomers (LMW-PAOs), including flavan-3-ol units such as catechin (C) and epicatechin (EC). Based on the ability of its various components to confer resilience to the onset of AD, we tested whether oligopin can specifically prevent or attenuate the progression of AD dementia preclinically. We also explored the underlying mechanism(s) through which oligopin may exert its biological activities. Oligopin inhibited oligomer formation of not only Aβ1-40 and Aβ1-42 , but also tau in vitro . Our pharmacokinetics analysis of metabolite accumulation in vivo resulted in the identification of Me-EC-O -β-Glucuronide, Me-(±)-C-O -β-glucuronide, EC-O -β-glucuronide, and (±)-C-O -β-glucuronide in the plasma of mice. These metabolites are primarily methylated and glucuronidated C and EC conjugates. The studies conducted provide the necessary impetus to design future clinical trials with bioactive oligopin to prevent both prodromal and residual forms of AD. Show more

Keywords: Alzheimer’s disease, amyloid β-peptide, polyphenols, tau

DOI: 10.3233/JAD-190543

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Tan, Chin Hong | Hilal, Saima | Xu, Xin | Vrooman, Henri | Cheng, Ching-Yu | Wong, Tien Yin | Venketasubramanian, Narayanaswamy | Chen, Christopher

Article Type: Research Article

Abstract: There is a need to elucidate the combined influence of neurodegeneration and cerebrovascular disease (CeVD) on cognitive impairment, especially in diverse populations. Here, we evaluated 840 multiethnic individuals (mean age = 70.18) across the disease spectrum in the Epidemiology of Dementia in Singapore study. First, we determined whether a validated quantitative MRI score of mixed pathology is associated with clinical diagnosis and whether the score differed between ethnicities (Chinese, Malays, and Indians). We then evaluated whether the score was associated with multidomain cognitive impairment and if additional measures of CeVD were further associated with cognitive impairment. We found that lower quantitative MRI …scores were associated with severity of clinical diagnosis and Chinese individuals had the highest quantitative MRI scores, followed by Indians and Malays. Lower quantitative MRI scores were also associated with lower performance in attention, language, visuoconstruction, visuomotor, visual, and verbal memory domains. Lastly, the presence of intracranial stenosis and cortical cerebral microinfarcts, but not cerebral microbleeds, were associated with memory performance beyond quantitative MRI scores. Taken together, our results demonstrate the utility of using multiple MRI markers of neurodegeneration and CeVD for identifying multiethnic Asians with the greatest cognitive impairment due to mixed pathology. Show more

Keywords: Alzheimer’s disease, cerebrovascular diseases, cognition, cortical cerebral microinfarcts, ethnicity, intracranial stenosis, magnetic resonance imaging, mixed dementia

DOI: 10.3233/JAD-190866

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Fernando, W.M.A.D. Binosha | Martins, Ian J. | Morici, Michael | Bharadwaj, Prashant | Rainey-Smith, Stephanie R. | Lim, Wei Ling Florence | Martins, Ralph N.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological features, including abnormal deposition of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles, and neuronal death. Identifying therapeutics which can reduce memory deficits at an early stage of the disease has the advantage of slowing or even reversing disease progression before irreversible brain damage has occurred. Consequently, in this study, we investigated the ability of the histone deacetylase inhibitor sodium butyrate (NaB) to attenuate memory deficits in the 5xFAD mouse model of AD following a 12-week feeding regimen. 5xFAD mice demonstrate a unique time course of Aβ pathology, …developing Aβ plaques as early as 2 months. Male mice were assigned to either a control diet or a NaB-supplemented diet which was administered at either 5 mg/kg/day, or 15 mg/kg/day for 12 weeks (each group, N = 15). Supplementation commenced at an early disease stage (8–10 weeks of age). Behavioral testing (contextual and cued fear conditioning) was undertaken, and brain Aβ levels measured, at the end of the 12-week intervention. NaB had profound effects on Aβ levels and on associative learning and cognitive functioning. A 40% reduction in brain Aβ levels and a 25% increase in fear response in both the cued and contextual testing was observed in the NaB-treated animals compared to the control group. These findings suggest that NaB warrants further investigation as a potential therapeutic agent in the treatment of cognitive deficits associated with early stages of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , fear conditioning, sodium butyrate

DOI: 10.3233/JAD-190120

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Tuzzi, Elisa | Balla, David Z. | Loureiro, Joana R.A. | Neumann, Manuela | Laske, Christoph | Pohmann, Rolf | Preische, Oliver | Scheffler, Klaus | Hagberg, Gisela E.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo . Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using …quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2 *) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo . Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2 * maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid plaque load, biomarkers, effective transverse relaxation rate, histology, quantitative susceptibility mapping, ultra-high field

DOI: 10.3233/JAD-190424

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Chintapaludi, Sumana R. | Uyar, Asli | Jackson, Harriet M. | Acklin, Casey J. | Wang, Xulong | Sasner, Michael | Carter, Gregory W. | Howell, Gareth R.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a common form of dementia characterized by amyloid plaque deposition, tau pathology, neuroinflammation, and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1 ) shows plaque deposition and neuroinflammation involving both astrocytes and microglia beginning around 4–6 months of age. However, significant tau pathology and neurodegeneration are not apparent in this model even when assessed at old age. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized …linear modeling (GLM), functional annotation followed by validation by immunofluorescence was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2–6 months of age). Multiple pathways were shown to be activated in response to amyloid deposition including the JAK/STAT and NALFD pathways. Putative, cell-specific targets of STAT3, a central component of the JAK/STAT pathway, were identified that we propose provide more precise options for assessing the potential for targeting activation of the JAK/STAT pathway as a treatment for human AD. In the retina, GLM predicted activation of vascular-related pathways. However, many of the gene expression changes comparing B6 with B6.APP/PS1 retina samples occurred prior to plaque onset (2 months of age). This suggests retinal changes in B6.APP/PS1 mice may be an artefact of overexpression of mutant forms of APP and PSEN1 providing limited translatability to human AD. Therefore, caution should be taken when using this mouse model to assess the potential of using the eye as a window to the brain for AD. Show more

Keywords: Alzheimer’s disease, amyloid, brain, generalized linear model, immunofluorescence, JAK/STAT, microhemorrhages, retina, RNA sequencing

DOI: 10.3233/JAD-190793

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019