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

Authors: Chen, Chih-Hao | Chen, Ya-Fang | Tsai, Ping-Huan | Chiou, Jeng-Min | Lai, Liang-Chuan | Chen, Ta-Fu | Hung, Hung | Chen, Jen-Hau | Chen, Yen-Ching

Article Type: Research Article

Abstract: Background: Cerebral cortical thickness is a neuroimaging biomarker to predict cognitive decline, and kidney dysfunction (KD) is associated with cortical thinning. Objective: This study aimed to investigate the effects of KD and cortical thinning on cognitive change in a prospective cohort study. Methods: A total of 244 non-demented participants were recruited from elderly health checkup program and received cognitive exams including Montreal Cognitive Assessment (MoCA) and different cognitive domains at baseline and three biannual follow-ups afterwards. KD was defined as having either glomerular filtration rate <60 ml/min/1.73 m2 or proteinuria. Cortical thickness of global, lobar, and Alzheimer’s …disease (AD) signature area were derived from magnetic resonance imaging at baseline, and cortical thinning was defined as the lowest tertile of cortical thickness. Generalized linear mixed models were applied to evaluate the effects of KD and cortical thinning on cognitive changes. Results: KD was significantly associated with the decline in attention function (β= –0.29). Thinning of global (β= –0.06), AD signature area (β= –0.06), temporal (β= –0.06), and parietal lobes (β= –0.06) predicted poor verbal fluency over time, while temporal lobe thinning also predicted poor MoCA score (β= –0.19). KD modified the relationship between thinning of global, frontal, and limbic, and change of logical memory function (p interaction  < 0.05). When considering jointly, participants with both KD and cortical thinning had greatest decline in attention function compared with those without KD or cortical thinning (β= –0.51, p trend  = 0.008). Conclusions: KD and cortical thinning have joint effect on cognitive decline, especially the attention function. Reverse associations may exist between cortical thinning and memory function in participants with KD, though the results should be interpreted cautiously as an exploratory analysis. Show more

Keywords: Cerebral cortex, cognition, glomerular filtration rate, proteinuria

DOI: 10.3233/JAD-200053

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 225-236, 2020

Authors: Shi, Yan | Gao, Feng | Yang, Xiaoli | Liu, Dongwei | Han, Qiuxia | Liu, Zhangsuo | Zhu, Hanyu | Shen, Yong

Article Type: Research Article

Abstract: Background: It is believed that there is a certain correlation between the brain and kidneys, but it is poorly understood. Many findings suggested that there were previously unknown signaling pathways involving AβPP and BACE1 in the kidney. Objective: Exploring the changes of BACE1 activity in APP23 mouse kidneys, providing evidence for the function of AβPP and BACE1 activity in the kidney. Methods: The activity and expression of BACE1 were detected in the kidney of APP23 mice by enzymatic assay and western blotting. The protein expression levels of AβPP, claudin1, occludin, VE-cadherin, and Klotho (membrane-form klotho) were …examined by using western blotting. The renal pathological changes of APP23 mice were examined by the routine renal pathological procedures. Results: In this study, we found that the AβPP protein level was increased in kidneys of APP23 mice compared with wild-type (WT) mice. Additionally, the activity and expression of BACE1 were increased in kidneys of APP23 mice compared to that of WT. BACE1 was predominantly distributed on the lumen side of renal tubular epithelial cells. The protein levels of Klotho and VE-cadherin were decreased, occludin expression was also decreased, and claudin-1 expression was increased. Renal pathological damage which observed in kidneys of APP23 mice was more serious than that in kidneys of WT mice. Conclusion: Our findings suggest that the increase of AβPP protein levels under Thy-1 neuron promoter in the APP23 mice promoted the increase of renal BACE1 expression and enzymatic activity in the kidneys. Moreover, certain pathological damage in the kidneys of APP23 mice were observed. APP23 mice are easily affected by external risk factors compared with WT mice. Show more

Keywords: Alzheimer’s disease, APP23, BACE1, brain-renal risk factor, kidney

DOI: 10.3233/JAD-200204

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 237-248, 2020

Authors: Yang, Kun | Chen, Guanqun | Sheng, Can | Xie, Yunyan | Li, Yuxia | Hu, Xiaochen | Sun, Yu | Han, Ying

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) and brain reserve (BR) could offer protective effects on cognition in the early stage of Alzheimer’s disease (AD). However, the effects of CR or BR on cognition in individuals with subjective cognitive decline (SCD) are not clear. Objective: To explore the effects of CR and BR on cognition in subjects with SCD. Methods: We included 149 subjects from the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Education was used as a proxy for CR, and head circumference was used as a proxy for BR. Multiple linear regression models were conducted to …examine the effects of CR and BR on cognitive scores. Furthermore, we assessed differences in effects between APOE ɛ 4 carriers with SCD (n  = 35) and APOE ɛ 4 non-carriers with SCD (n  = 114) and linear trends among 4 reserve levels (low BR/CR, high BR/low CR, low BR/high CR, and high BR/high CR). Results: Both CR and BR had independent positive effects on multiple cognitive measures in SCD participants, and the effects of CR were greater than those of BR. CR has positive effects on cognitive measures in both APOE ɛ 4 carriers and non-carriers with SCD. However, the positive effects of BR on cognitive measures were observed in APOE ɛ 4 non-carriers with SCD but not in APOE ɛ 4 carriers with SCD. Furthermore, there was a linear trend toward better cognitive performance on all cognitive measures in the BR+/CR+ group, followed by the BR–/CR+, BR+/CR–, and BR–/CR–groups. Conclusion: This study suggests that both CR and BR have the potential to delay or slow cognitive decline in individuals with SCD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, brain reserve, cognition, cognitive reserve, dementia, education, head circumference, reserve, subjective cognitive decline

DOI: 10.3233/JAD-200082

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 249-260, 2020

Authors: Stricker, Nikki H. | Lundt, Emily S. | Albertson, Sabrina M. | Machulda, Mary M. | Pudumjee, Shehroo B. | Kremers, Walter K. | Jack Jr., Clifford R. | Knopman, David S. | Petersen, Ronald C. | Mielke, Michelle M.

Article Type: Research Article

Abstract: Background: There are detectable cognitive differences in cognitively unimpaired (CU) individuals with preclinical Alzheimer’s disease (AD). Objective: To determine whether cross-sectional performance on the Cogstate Brief Battery (CBB) and Auditory Verbal Learning Test (AVLT) could identify 1) CU participants with preclinical AD defined by neuroimaging biomarkers of amyloid and tau, and 2) incident mild cognitive impairment (MCI)/dementia. Method: CU participants age 50+ were eligible if they had 1) amyloid (A) and tau (T) imaging within two years of their baseline CBB or 2) at least one follow-up visit. AUROC analyses assessed the ability of measures to …differentiate groups. We explored the frequency of cross-sectional subtle objective cognitive impairment (sOBJ) defined as performance ≤–1 SD on CBB Learning/Working Memory Composite (Lrn/WM) or AVLT delayed recall using age-corrected normative data. Results: A+T+ (n  = 33, mean age 79.5) and A+T– (n  = 61, mean age 77.8) participants were older than A–T– participants (n  = 146, mean age 66.3), and comparable on sex and education. Lrn/WM did not differentiate A  + T+or A+T– from A–T– participants. AVLT differentiated both A+T+ and A+T– from A–T– participants; 45% of A+T+ and 25% of A+T– participants met sOBJ criteria. The follow-up cohort included 150 CU individuals who converted to MCI/dementia and 450 age, sex, and education matched controls. Lrn/WM and AVLT differentiated between stable and converter CU participants. Conclusion: Among CU participants, AVLT helped differentiate A+T+ and A+T– from A–T– participants. The CBB did not differentiate biomarker subgroups, but showed potential for predicting incident MCI/dementia. Results inform future definitions of sOBJ. Show more

Keywords: Amyloid, Cognigram, conversion, memory, neuropsychology, one back, one card learning, sensitivity and specificity, subtle cognitive decline, tau

DOI: 10.3233/JAD-200087

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 261-274, 2020

Authors: Raji, Cyrus A. | Meysami, Somayeh | Merrill, David A. | Porter, Verna R. | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: Bilingualism is increasingly recognized as protective in persons at risk for Alzheimer’s disease (AD). Objective: Compare MRI measured brain volumes in matched bilinguals versus monolinguals with AD. Methods: This IRB approved study analyzed T1 volumetric brain MRIs of patients with criteria-supported Probable AD. We identified 17 sequential bilinguals (any native language) with Probable AD, matched to 28 (62%) monolinguals on age and MMSE. Brain volumes were quantified with Neuroreader. Regional volumes as fraction of total intracranial volume (TIV) were compared between both groups, and Cohen’s D effect sizes were calculated for statistically significant structures. Partial …correlations between bilingualism and brain volumes adjusted for age, gender, and TIV. Results: Bilinguals had higher brain volumes in 37 structures. Statistical significance (p  < 0.05) was observed in brainstem (t  = 2.33, p  = 0.02, Cohen’s D  = 0.71) and ventral diencephalon (t  = 3.01, p  = 0.004, Cohen’s D  = 0.91). Partial correlations showed statistical significance between bilingualism and larger volumes in brainstem (rp  = 0 .  37, p  = 0.01), thalamus (rp  = 0.31, p  = 0.04), ventral diencephalon (rp  = 0.50, p  = 0.001), and pallidum (rp  = 0.38, p  = 0.01). Bilingualism positively correlated with hippocampal volume, though not statistically significant (rp  = 0.17, p  = 0.26). No brain volumes were larger in monolinguals. Conclusion: Bilinguals demonstrated larger thalamic, ventral diencephalon, and brainstem volumes compared to matched monolinguals with AD. This may represent a neural substrate for increased cognitive reserve in bilingualism. Future studies should extrapolate this finding into cognitively normal persons at risk for AD. Show more

Keywords: Alzheimer’s disease, bilingual, brain structure, Neuroreader

DOI: 10.3233/JAD-200200

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 275-280, 2020

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. 76, no. 1, pp. 281-290, 2020

Authors: Chatterjee, Pratishtha | Mohammadi, Maryam | Goozee, Kathryn | Shah, Tejal M. | Sohrabi, Hamid R. | Dias, Cintia B. | Shen, Kaikai | Asih, Prita R. | Dave, Preeti | Pedrini, Steve | Ashton, Nicholas J. | Hye, Abdul | Taddei, Kevin | Lovejoy, David B. | Zetterberg, Henrik | Blennow, Kaj | Martins, Ralph N.

Article Type: Research Article

Abstract: Background/Objective: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer’s disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-β load (NAL). Methods: Serum hepcidin levels in cognitively normal participants (n  = 100) aged between 65–90 years were measured using ELISA. To evaluate NAL, all …participants underwent 18 F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)<1.35 was classified as low NAL (n  = 65) and ≥1.35 (n  = 35) was classified as high NAL. Results: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOE ɛ 4 carriage (p  < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma Aβ42/40 ratio (AUC = 0.829). Conclusion: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required. Show more

Keywords: Alzheimer’s disease, amyloid deposits, hepcidin, iron dyshomeostasis, positron emission tomography

DOI: 10.3233/JAD-200162

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 291-301, 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. 76, no. 1, pp. 303-315, 2020

Authors: Traini, Enea | Carotenuto, Anna | Fasanaro, Angiola Maria | Amenta, Francesco

Article Type: Research Article

Abstract: Background: Cerebral atrophy is a common feature of several neurodegenerative disorders, including Alzheimer’s disease (AD). In AD, brain atrophy is associated with loss of gyri and sulci in the temporal and parietal lobes, and in parts of the frontal cortex and cingulate gyrus. Objective: The ASCOMALVA trial has assessed, in addition to neuropsychological analysis, whether the addition of the cholinergic precursor choline alphoscerate to treatment with donepezil has an effect on brain volume loss in patients affected by AD associated with cerebrovascular injury. Methods: 56 participants to the randomized, placebo-controlled, double-blind ASCOMALVA trial were assigned to …donepezil + placebo (D + P) or donepezil + choline alphoscerate (D + CA) treatments and underwent brain magnetic resonance imaging and neuropsychological tests every year for 4 years. An interim analysis of 3-year MRI data was performed by voxel morphometry techniques. Results: The D + P group (n  = 27) developed atrophy of the gray and white matter with concomitant increase in ventricular space volume. In the D + CA group (n  = 29) the gray matter atrophy was less pronounced compared to the D + P group in frontal and temporal lobes, hippocampus, and amygdala. These morphological data are consistent with the results of the neuropsychological tests. Conclusion: Our findings indicate that the addition of choline alphoscerate to standard treatment with the cholinesterase inhibitor donepezil counters to some extent the loss in volume occurring in some brain areas of AD patients. The observation of parallel less pronounced decrease in cognitive and functional tests in patients with the same treatment suggests that the morphological changes observed may have functional relevance. Show more

Keywords: Alzheimer’s disease, association, brain atrophy, cerebrovascular injury, choline alphoscerate, donepezil

DOI: 10.3233/JAD-190623

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 317-329, 2020

Authors: Nicastro, Nicolas | Malpetti, Maura | Cope, Thomas E. | Bevan-Jones, William Richard | Mak, Elijah | Passamonti, Luca | Rowe, James B. | O’Brien, John T.

Article Type: Research Article

Abstract: Background: The changes of cortical structure in Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are usually described in terms of atrophy. However, neurodegenerative diseases may also affect the complexity of cortical shape, such as the fractal dimension of the brain surface. Objective: In this study, we aimed at assessing the regional patterns of cortical thickness and fractal dimension changes in a cross-sectional cohort of patients with AD and FTD. Methods: Thirty-two people with symptomatic AD-pathology (clinically probable AD, n  = 18, and amyloid-positive mild cognitive impairment, n  = 14), 24 with FTD and 28 healthy controls underwent high-resolution …3T structural brain MRI. Using surface-based morphometry, we created vertex-wise cortical thickness and fractal dimension maps for group comparisons and correlations with cognitive measures in AD and FTD. Results: In addition to the well-established pattern of cortical thinning encompassing temporoparietal regions in AD and frontotemporal areas in FTD, we observed reductions of fractal dimension encompassing cingulate areas and insula for both conditions, but specifically involving orbitofrontal cortex and paracentral gyrus for FTD (FDR p  < 0.05). Correlational analyses between fractal dimension and cognition showed that these regions were particularly vulnerable with regards to memory and language impairment, especially in FTD. Conclusion: While the present study demonstrates globally similar patterns of fractal dimension changes in AD and FTD, we observed distinct cortical complexity correlates of cognitive domains impairment. Further studies are required to assess cortical complexity measures at earlier disease stages (e.g., in prodromal/asymptomatic carriers of FTD-related gene mutations) and determine whether fractal dimension represents a sensitive imaging marker for prevention and diagnostic strategies. Show more

Keywords: Alzheimer’s disease, cortical thickness, dementia, fractal dimension, frontotemporal dementia, magnetic resonance imaging

DOI: 10.3233/JAD-200246

Citation: Journal of Alzheimer's Disease, vol. 76, no. 1, pp. 331-340, 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. 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