Journal of Alzheimer's Disease - Volume 76, issue 1

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. 76, no. 1, pp. 341-347, 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. 76, no. 1, pp. 349-368, 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. 76, no. 1, pp. 369-385, 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: Attention, dietary supplements, hops, subjective cognitive decline

DOI: 10.3233/JAD-200229

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 387-398, 2020

Authors: Sherman, Dale S. | Durbin, Kelly A. | Ross, David M.

Article Type: Research Article

Abstract: Background: Meta-analysis examining the efficacy of cognitive interventions on neuropsychological outcomes have suggested interventions that focus on memory may actually provide greater benefit against the cognitive declines associated with mild cognitive impairment (MCI). However, it remains unclear if memory-based training would be more effective at addressing the cognitive deficits associated with MCI than multidomain forms of intervention. Objective: A meta-analytic review and subgroup analysis was conducted to examine the effects of cognitive training in individuals diagnosed with MCI and to compare the efficacy of memory-based training with multidomain interventions. Methods: A total of 32 randomized controlled …trials met inclusion criteria for the meta-analysis, which included 9 studies on memory-focused training and 17 studies on multidomain interventions. Results: We found significant, large effects for memory-focused training (Hedges’ g observed = 0.947; 95% CI [–1.668, 3.562]; Z  = 2.517; p  = 0.012) and significant, moderate effects for multidomain interventions (Hedges’ g observed = 0.420; 95% CI [–0.4491, 1.2891]; Z  = 3.525; p  < 0.001). A subgroup analysis found significant point estimates for memory-based forms of training and multidomain interventions, with memory-based forms of content yielding significantly greater summary effects than multidomain interventions (SMD Z  = 2.162; p  = 0.031, two-tailed; all outcomes). There was no difference between effect sizes when comparing outcomes limited to its respective domain. Conclusion: Overall, these findings suggest that, while both interventions were beneficial, treatment interventions that were strictly memory-based were more effective at improving cognition in individuals diagnosed with MCI than interventions that targeted multiple cognitive domains. Show more

Keywords: Cognitive dysfunction, cognitive remediation, meta-analysis, neuropsychology, rehabilitation

DOI: 10.3233/JAD-200261

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 399-421, 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 Aβ40 -induced toxicity in human primary astrocytes. Methods: The protective …effect of bacterial secondary metabolites against Aβ40 -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 Aβ40 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 Aβ40 . 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. 76, no. 1, pp. 423-433, 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. 76, no. 1, pp. 435-442, 2020