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

Authors: Cho, Soo Hyun | Choe, Yeong Sim | Kim, Young Ju | Kim, Hee Jin | Jang, Hyemin | Kim, Yeshin | Kim, Si Eun | Kim, Seung Joo | Kim, Jun Pyo | Jung, Young Hee | Kim, Byeong C. | Lockhart, Samuel N. | Farrar, Gill | Na, Duk L. | Moon, Seung Hwan | Seo, Sang Won

Article Type: Research Article

Abstract: Background: 18 F-florbetaben (FBB) and 18 F-flutemetamol (FMM) amyloid PET have been developed and approved for clinical use. It is important to understand the distinct features of these ligands to compare and correctly interpret the results of different amyloid PET studies. Objective: We performed a head-to-head comparison of FBB and FMM to compare with regard to imaging characteristics, including dynamic range of retention, and differences in quantitative measurements between the two ligands in cortical, striatal, and white matter (WM) regions. Methods: Paired FBB and FMM PET images were acquired in 107 participants. Correlations of FBB and …FMM amyloid deposition in the cortex, striatum, and WM were investigated and compared in different reference regions (cerebellar gray matter (CG), whole cerebellum (WC), WC with brainstem (WC + B), and pons). Results: The cortical SUVR (R2  = 0.97) and striatal SUVR (R2  = 0.95) demonstrated an excellent linear correlation between FBB and FMM using a WC as reference region. There was no difference in the cortical SUVR ratio between the two ligands (p  = 0.90), but the striatal SUVR ratio was higher in FMM than in FBB (p  < 0.001). Also, the effect size of differences in striatal SUVR seemed to be higher with FMM (2.61) than with FBB (2.34). These trends were similarly observed according to four different reference regions (CG, WC, WC + B, and pons). Conclusion: Our findings suggest that FMM might be better than FBB to detect amyloid burden in the striatum, although both ligands are comparable for imaging AD pathology in vivo . Show more

Keywords: Alzheimer’s disease, amyloid imaging, 18F-florbetaben, 18F-flutemetamol, head to head

DOI: 10.3233/JAD-200079

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Rabipour, Sheida | Rajagopal, Sricharana | Yu, Elsa | Pasvanis, Stamatoula | Lafaille-Magnan, Marie-Elyse | Breitner, John | PREVENT-AD Research Group | Rajah, M. Natasha

Article Type: Research Article

Abstract: Background: Episodic memory decline is one of the earliest symptoms of late-onset Alzheimer’s disease (AD). Older adults with the apolipoprotein E ɛ 4 (+APOE4 ) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset. Objective: Here we report the baseline episodic memory task functional MRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer’s Disease cohort in Montreal, Canada, in which 327 healthy older adults were scanned within 15 years of their parent’s conversion to AD. Methods: Volunteers were scanned as they encoded …and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to spatial source recollection and object-only (recognition) memory. We used multivariate partial least squares to test the hypothesis that +APOE4 adults with family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal, and medial temporal cortices, compared to APOE4 non-carriers (–APOE4 ). We also examined group differences in the correlation between event-related brain activity and memory performance. Results: We found group similarities in memory performance and in task-related brain activity in the recollection network, but differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding. Conclusion: These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with first-degree family history of AD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E polymorphism, associative learning, brain-behavior relationships, episodic memory, familial history, task-related functional MRI

DOI: 10.3233/JAD-191292

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2020

Authors: Picillo, Marina | Vitale, Emilia | Rendina, Antonella | Donizetti, Aldo | Aliperti, Vincenza | Tepedino, Maria Francesca | Dati, Giovanna | Ginevrino, Monia | Valente, Enza Maria | Barone, Paolo

Article Type: Research Article

Abstract: Background: Mutations in the GRN gene are causative for an autosomal dominant form of frontotemporal dementia. Objective/Methods: The objective of the present study is to describe clinical and molecular features of three siblings harboring the GRN deletion NM_002087.3:c.295_308delTGCCCACGGGGCTT, p.(Cys99Profs*15) identified with next generation sequencing. Results: Our patients demonstrated heterogeneous clinical phenotypes, such as progressive supranuclear palsy-like in the proband and the behavioral variant of frontotemporal dementia in the two affected siblings. Progranulin haploinsufficiency was revealed by both gene expression and protein analyses. Conclusion: The pathogenicity of the novel GRN deletion c.295_308del …TGCCCACGGGGCTT is confirmed by both functional analysis and segregation in three affected siblings. Show more

Keywords: Dementia, gene, genetics, parkinsonism, progranulin, progressive supranuclear palsy

DOI: 10.3233/JAD-200151

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Benhamron, Sandrine | Nitzan, Keren | Valitsky, Michael | Lax, Neta | Karussis, Dimitrios | Kassis, Ibrahim | Rosenmann, Hanna

Article Type: Research Article

Abstract: Background: The high complexity of neurodegenerative diseases, including Alzheimer’s disease (AD), and the lack of effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. Objective: To test the efficacy of ‘cerebrospinal fluid (CSF) exchange therapy’ in AD-mice. This novel therapeutic approach we recently proposed is based on the exchange of the endogenous pathogenic CSF with a new and healthy one by drainage of the endogenous CSF and its continuous replacement with artificial CSF (aCSF) enriched with secretions from human mesenchymal stem cells (MSCs). Methods: We …treated AD-mice (amyloid-beta injected) with MSC secretions-enriched-aCSF using an intracerebroventricular CSF exchange procedure. Cognitive and histological analysis were performed. Results: We show that the MSC secretions enriched CSF exchange therapy improved cognitive performance, paralleled with increased neuronal counts (NeuN positive cells), reduced astrocytic burden (GFAP positive cells), and increased cell proliferation and neurogenesis (Ki67 positive cells and DCX positive cells) in the hippocampus. This beneficial effect was noted on days 5–10 following 3-consecutive daily exchange treatments (3 hours a day). A stronger effect was noted using a more prolonged CSF exchange protocol (3-consecutive daily exchange treatments with 3 additional treatments twice weekly), with cognitive follow-up performed as early as 2–3 days after treatment. Some increase in hippocampal cell proliferation, but no change in the other histological parameters, was noticed when performing CSF exchange therapy using unenriched aCSF relative to untreated AD-mice, yet smaller than with the enriched aCSF treatment. Conclusion: These findings point to the therapeutic potential of the CSF exchange therapy using MSC secretions-enriched aCSF in AD, and might be applied to other neurodegenerative and dementia diseases. Show more

Keywords: Alzheimer’s disease, artificial CSF, CSF exchange therapy, mesenchymal stem cells, mesenchymal stem cell secretions, mice

DOI: 10.3233/JAD-191219

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Dehhaghi, Mona | Kazemi Shariat Panahi, Hamed | Braidy, Nady | Guillemin, Gilles J.

Article Type: Research Article

Abstract: Background: The accumulation of extracellular plaques containing amyloid-β protein (Aβ ) in the brain is one of the main pathological hallmarks of Alzheimer’s disease (AD). Aβ peptide can promote the production of highly volatile free radicals and reactive oxygen species (ROS) that can induce oxidative damage to neurons and astrocytes. At present, numerous studies have investigated the neuroprotective and glioprotective effects of natural products derived from plants, animals, and microorganisms. Objective: We investigated the glioprotective effect of secondary metabolites obtained from Herpetosiphon sp. HM 1988 against Aβ 40 -induced toxicity in human primary astrocytes. …Methods: The protective effect of bacterial secondary metabolites against Aβ 40 -induced inducible nitric oxide synthase (iNOS) activity was evaluated using the citrulline assay. To confirm the iNOS activity, nitrite production was assessed using the fluorometric Griess diazotization assay. Intracellular NAD+ depletion and lactate dehydrogenase (LDH) release in human primary astrocytes were also examined using well-established spectrophotometric assays. Results: Our results indicate that Aβ 40 can induce elevation in iNOS and LDH activities, nitrite production, and cellular energy depletion. Importantly, extract of Herpetosiphon sp. HM 1988 decreased iNOS activity, nitrite production, and LDH release. In addition, metabolites of the strain were able to restore cellular energy deficits through inhibition of NAD+ depletion mediated by Aβ 40 . Conclusion: These findings suggest that Herpetosiphon metabolites may represent a promising, novel source for the prevention of Aβ toxicity in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , Herpetosiphon , inducible nitric oxide synthase, natural products, oxidative stress

DOI: 10.3233/JAD-200116

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Umegaki, Hiroyuki | Bonfiglio, Viviana | Komiya, Hitoshi | Watanabe, Kazuhisa | Kuzuya, Masafumi

Article Type: Research Article

Abstract: Background: Cognitive impairment is linked to decreased quality of life (QOL), but few studies have investigated the impact of comorbid sarcopenia. Objective: The aim of this study was to elucidate the association of sarcopenia with QOL in patients with early dementia and mild cognitive impairment. Methods: Individuals with a Clinical Dementia Rating of 0.5 or 1 and a Mini-Mental State Examination score of 20–30 underwent a battery of neuropsychological assessments administered by a group of well-trained clinical psychologists. The EQ-5D was completed by both the patients and their main caregivers. EQ-5D utility and visual analog scale …scores were measured. Sarcopenia was defined according to the criteria published in the 2019 consensus update by the Asian Working Group for Sarcopenia. Results: Patients with sarcopenia had significantly lower scores on the Digit Symbol Substitution Test and Trail Making Test Part A. There was a significant negative association between sarcopenia and both self- and proxy-rated EQ-5D utility scores independent of potential confounding factors. However, there was no association between QOL visual analog scale scores and sarcopenia. Conclusion: Given that sarcopenia is often found in individuals with cognitive impairment, early detection by timely screening and effective intervention may help to maintain or improve QOL in this population. However, this study could not determine whether reduced QOL is a direct consequence of sarcopenia. Show more

Keywords: Cognitive dysfunction, gait speed, grip, sarcopenia

DOI: 10.3233/JAD-200169

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Fukuda, Takafumi | Ohnuma, Tohru | Obara, Kuniaki | Kondo, Sumio | Arai, Heii | Ano, Yasuhisa

Article Type: Research Article

Abstract: Background: Prevention of age-related cognitive decline and depression is becoming urgent because of rapid growing aging populations. Effects of vagal nerve activation on brain function by food ingredients are inadequately investigated; matured hop bitter acid (MHBA) administration reportedly improves cognitive function and depression via vagal nerve activation in model mice. Objective: We investigated the effects of MHBA supplementation on cognitive function and mood state in healthy older adults with perceived subjective cognitive decline. Methods: Using a randomized double-blind placebo-controlled trial design, 100 subjects (aged 45–69 years) were randomly assigned into placebo (n  = 50) and MHBA (n … = 50) groups, and received placebo or MHBA capsules daily for 12 weeks. Results: Symbol Digit Modalities Test (SDMT) score assessing divided attention at week 12 was significantly higher (p  = 0.045) and β -endorphin at week 12 was significantly lower (p  = 0.043) in the subjects receiving MHBA. Transthyretin in serum, a putative mild cognitive impairment marker, was significantly higher at week 12 in the MHBA group than in the placebo group (p  = 0.048). Subgroup analysis classified by the subjective cognitive decline questionnaire revealed that in addition to improved SDMT scores, memory retrieval assessed using the standard verbal paired-associate learning tests and the Ray Verbal Learning Test at week 12 had significantly improved in the subgroup with perceived subjective cognitive decline and without requirement for medical assistance in the MHBA group compared with that in the placebo group. Conclusion: This study suggested that MHBA intake improves cognitive function, attention, and mood state in older adults. Show more

Keywords: Brain, cognitive dysfunction, dietary supplements, paired-associate learning

DOI: 10.3233/JAD-200229

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Chen, Mei | Xia, Weiming

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most prevalent form of dementia with two pathological hallmarks of tau-containing neurofibrillary tangles and amyloid-β protein (Aβ )-containing neuritic plaques. Although Aβ and tau have been explored as potential biomarkers, levels of these pathological proteins in blood fail to distinguish AD from healthy control subjects. Objective: We aim to discover potential plasma proteins associated with AD pathology by performing tandem mass tag (TMT)-based quantitative proteomic analysis of proteins from peripheral and central nervous system compartments. Methods: We performed comparative proteomic analyses of plasma collected from AD patients and …cognitively normal subjects. In addition, proteomic profiles from the inferior frontal cortex, superior frontal cortex, and cerebellum of postmortem brain tissue from five AD patients and five non-AD controls were compared with plasma proteomic profiles to search for common biomarkers. Liquid chromatography-mass spectrometry was used to analyze plasma and brain tissue labeled with isobaric TMT for relative protein quantification. Results: Our results showed that the proteins in complement coagulation cascade and interleukin-6 signaling were significantly altered in both plasma and brains of AD patients. Conclusion: Our results demonstrate the relevance in immune responses between the peripheral and central nervous systems. Those differentially regulated plasma proteins are explored as candidate biomarker profiles that illustrate chronic neuroinflammation in brains of AD patients. Show more

Keywords: Alzheimer’s disease, biomarker, mass spectrometry, plasma, quantitative proteomics, tandem mass tag (TMT)

DOI: 10.3233/JAD-200110

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2020

Authors: Lim, Wei Ling Florence | Huynh, Kevin | Chatterjee, Pratishtha | Martins, Ian | Jayawardana, Kaushala S. | Giles, Corey | Mellett, Natalie A. | Laws, Simon M. | Bush, Ashley I. | Rowe, Christopher C. | Villemagne, Victor L. | Ames, David | Drew, Brian G. | Masters, Colin L. | Meikle, Peter J. | Martins, Ralph N. | AIBL research group

Article Type: Research Article

Abstract: Background: Lipid metabolism is altered in Alzheimer’s disease (AD); however, the relationship between AD risk factors (age, APOE ɛ 4, and gender) and lipid metabolism is not well defined. Objective: We investigated whether altered lipid metabolism associated with increased age, gender, and APOE status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals. Methods: We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and …interaction analysis were used to explore the relationship between risk factors and plasma lipid species. Results: We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, APOE ɛ 4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and APOE ɛ 4 may, in part, be mediated by changes in lipid metabolism. Conclusion: This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways. Show more

Keywords: Aging, Alzheimer’s disease, APOE ɛ4, gender, lipid species

DOI: 10.3233/JAD-191304

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

Authors: Akhter, Firoz | Chen, Doris | Akhter, Asma | Sosunov, Alexander A. | Chen, Allen | McKhann, Guy M. | Yan, Shi Fang | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Background: Advanced glycation end products (AGEs) are an important risk factor for the development of cognitive decline in aging and late-onset neurodegenerative diseases including Alzheimer’s disease. However, whether and how dietary AGEs exacerbate cognitive impairment and brain mitochondrial dysfunction in the aging process remains largely unknown. Objective: We investigated the direct effects of dietary AGEs on AGE adducts accumulation, mitochondrial function, and cognitive performance in mice. Methods: Mice were fed the AGE+ diet or AGE–diet. We examined levels of AGE adducts in serum and cerebral cortexes by immunodetection and immunohistochemistry, determined levels of reactive oxygen species …by biochemical analysis, detected enzyme activity associated with mitochondrial respiratory chain complexes I & IV and ATP levels, and assessed learning and memory ability with Morris Water Maze and Nesting Behavior study. Results: Levels of AGE adducts (MG-H1 and CEL) were robustly increased in the serum and brain of AGE+ diet fed mice compared to AGE–group. Furthermore, greatly elevated levels of reactive oxygen species, decreased activities of mitochondrial respiratory chain complexes I & IV, reduced ATP levels, and impaired learning and memory were evident in AGE+ diet fed mice compared to AGE–group. Conclusion: These results indicate that dietary AGEs are important sources of AGE accumulation in vivo , resulting in mitochondrial dysfunction, impairment of energy metabolism, and subsequent cognitive impairment. Thus, reducing AGEs intake to lower accumulation of AGEs could hold therapeutic potential for the prevention and treatment of AGEs-induced mitochondrial dysfunction linked to cognitive decline. Show more

Keywords: Advanced glycation end-products, methylglyoxal, mitochondrial and cognitive dysfunction

DOI: 10.3233/JAD-191236

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020