Journal of Alzheimer's Disease - Volume 81, issue 3

Authors: Li, Wei-hao | Gan, Lin-hua | Ma, Fang-fang | Feng, Rui-li | Wang, Jiao | Li, Yan-hui | Sun, Yang-yang | Wang, Ya-jiang | Diao, Xin | Qian, Fei-yang | Wen, Tie-qiao

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease. One of the pathologies of AD is the accumulation of amyloid-β (Aβ) to form senile plaques, leading to a decline in cognitive ability and a lack of learning and memory. However, the cause leading to Aβ aggregation is not well understood. Dendritic cell factor 1 (Dcf1) shows a high expression in the entorhinal cortex neurons and neurofibrillary tangles in AD patients. Objective: Our goal is to investigate the effect of Dcf1 on Aβ aggregation and memory deficits in AD development. Methods: The mouse and Drosophila AD model …were used to test the expression and aggregation of Aβ, senile plaque formation, and pathological changes in cognitive behavior during dcf1 knockout and expression. We finally explored possible drug target effects through intracerebroventricular delivery of Dcf1 antibodies. Results: Deletion of Dcf1 resulted in decreased Aβ42 level and deposition, and rescued AMPA Receptor (GluA2) levels in the hippocampus of APP-PS1-AD mice. In Aβ42 AD Drosophila, the expression of Dcf1 in Aβ42 AD flies aggravated the formation and accumulation of senile plaques, significantly reduced its climbing ability and learning-memory. Data analysis from all 20 donors with and without AD patients aged between 80 and 90 indicated a high-level expression of Dcf1 in the temporal neocortex. Dcf1 contributed to Aβ aggregation by UV spectroscopy assay. Intracerebroventricular delivery of Dcf1 antibodies in the hippocampus reduced the area of senile plaques and reversed learning and memory deficits in APP-PS1-AD mice. Conclusion: Dcf1 causes Aβ-plaque accumulation, inhibiting dcf1 expression could potentially offer therapeutic avenues. Show more

Keywords: Alzheimer’s disease, amyloid-β, Dcf1, senile plaques

DOI: 10.3233/JAD-200619

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1181-1194, 2021

Authors: Szegeczki, Vince | Perényi, Helga | Horváth, Gabriella | Hinnah, Barbara | Tamás, Andrea | Radák, Zsolt | Ábrahám, Dóra | Zákány, Róza | Reglodi, Dóra | Juhász, Tamás

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative illness, with several peripheral pathological signs such as accumulation of amyloid-β (Aβ) plaques in the kidney. Alterations of transforming growth factor β (TGFβ) signaling in the kidney can induce fibrosis, thus disturbing the elimination of Aβ. Objective: A protective role of increased physical activity has been proven in AD and in kidney fibrosis, but it is not clear whether TGFβ signalization is involved in this effect. Methods: The effects of long-term training on fibrosis were investigated in the kidneys of mice representing a model of AD (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) by comparing …wild type and AD organs. Alterations of canonical and non-canonical TGFβ signaling pathways were followed with PCR, western blot, and immunohistochemistry. Results: Accumulation of collagen type I and interstitial fibrosis were reduced in kidneys of AD mice after long-term training. AD induced the activation of canonical and non-canonical TGFβ pathways in non-trained mice, while expression levels of signal molecules of both TGFβ pathways became normalized in trained AD mice. Decreased amounts of phosphoproteins with molecular weight corresponding to that of tau and the cleaved C-terminal of AβPP were detected upon exercising, along with a significant increase of PP2A catalytic subunit expression. Conclusion: Our data suggest that physical training has beneficial effects on fibrosis formation in kidneys of AD mice and TGFβ signaling plays a role in this phenomenon. Show more

Keywords: Alzheimer’s disease, fibrosis, physical activity, Smad, TGFβ

DOI: 10.3233/JAD-201206

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1195-1209, 2021

Authors: Perła-Kaján, Joanna | Włoczkowska, Olga | Zioła-Frankowska, Anetta | Frankowski, Marcin | Smith, A. David | de Jager, Celeste A. | Refsum, Helga | Jakubowski, Hieronim

Article Type: Research Article

Abstract: Background: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer’s disease. Objective: We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI). Methods: Individuals with MCI (n  = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) …(n  = 95) or placebo (n  = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n  = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates. Results: In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N -Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition. Conclusion: PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI. Show more

Keywords: BDNF V66M genotype, brain atrophy, cognition, iron, mild cognitive impairment, paraoxon, phenyl acetate, PON1 activity, PON1 Q192R genotype

DOI: 10.3233/JAD-210137

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1211-1229, 2021

Authors: Guzman-Martinez, Leonardo | Farías, Gonzalo A. | Tapia, José P. | Sánchez, María P. | Fuentes, Patricio | Gloger, Sergio | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Background: Clinically-evaluated nutraceuticals are candidates for Alzheimer’s disease (AD) prevention and treatment. Phase I studies showed biological safety of the nutraceutical BrainUp-10®, while a pilot trial demonstrated efficacy for treatment. Cell studies demonstrated neuroprotection. BrainUp-10® blocks tau self-assembly. Apathy is the most common of behavioral alterations. Objective: The aim was to explore efficacy of BrainUp-10® in mitigating cognitive and behavioral symptoms and in providing life quality, in a cohort of Chilean patients with mild to moderate AD. Methods: The was a multicenter, randomized, double blind, placebo-controlled phase II clinical study in mild to moderate AD patients …treated with BrainUp-10® daily, while controls received a placebo. Primary endpoint was Apathy (AES scale), while secondary endpoints included Mini-Mental State Examination (MMSE), Trail Making Test (TMT A and TMT B), and Neuropsychiatry Index (NPI). AD blood biomarkers were analyzed. Laboratory tests were applied to all subjects. Results: 82 patients were enrolled. The MMSE score improved significantly at week 24 compared to baseline with tendency to increase, which met the pre-defined superiority criteria. NPI scores improved, the same for caregiver distress at 12th week (p  = 0.0557), and the alimentary response (p  = 0.0333). Apathy tests showed a statistically significant decrease in group treated with BrainUp-10®, with p  = 0.0321 at week 4 and p  = 0.0480 at week 12 treatment. A marked decrease in homocysteine was shown with BrainUp-10® (p  = 0.0222). Conclusion: Data show that BrainUp-10® produces a statistically significant improvement in apathy, ameliorating neuropsychiatric distress of patients. There were no compound-related adverse events. BrainUp-10® technology may enable patients to receive the benefits for their cognitive and behavioral problems. Show more

Keywords: Alzheimer’s disease, blood biomarkers, BrainUp-10®, clinical trial, nutraceutical compound

DOI: 10.3233/JAD-201501

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1231-1241, 2021

Authors: Plácido, Jessica | Ferreira, José Vinicius | Araújo, Juliana | Silva, Felipe de Oliveira | Ferreira, Renan Baltar | Guimarães, Carla | de Carvalho, Andréa Nunes | Laks, Jerson | Deslandes, Andrea Camaz

Article Type: Research Article

Abstract: Background: Spatial navigation and dual-task (DT) performance may represent a low-cost approach to the identification of the cognitive decline in older adults and may support the clinical diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: To assess the accuracy of different types of motor tasks in differentiating older persons with MCI and AD from healthy peers. Methods: Older adults aged 60 years or over (n  = 105; healthy = 39; MCI = 23; AD = 43) were evaluated by the floor maze test (FMT), the senior fitness test, and DT performance. Receiver operating characteristic curve (ROC) analysis was used to …evaluate the accuracy of the tests. We also performed principal component analysis (PCA) and logistic regression analysis to explore the variance and possible associations of the variables within the sample. Results: FMT (AUC = 0.84, sensitivity = 75.7%, specificity = 76.1%, p  < 0.001) and DT (AUC = 0.87, sensitivity = 80.4%, specificity = 86.9%, p  < 0.001) showed the highest performance for distinguishing MCI from AD individuals. Moreover, FMT presented better sensitivity in distinguishing AD patients from their healthy peers (AUC = 0.93, sensitivity = 94%, specificity = 85.6%, p  < 0.001) when compared to the Mini-Mental State Examination. PCA revealed that the motor test performance explains a total of 73.9% of the variance of the sample. Additionally, the results of the motor tests were not influenced by age and education. Conclusion: Spatial navigation tests showed better accuracy than usual cognitive screening tests in distinguishing patients with neurocognitive disorders. Show more

Keywords: Aerobic capacity, Alzheimer’s disease, biomarkers, dual-task, floor maze test, mild cognitive impairment, physical fitness, spatial navigation

DOI: 10.3233/JAD-210106

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1243-1252, 2021

Authors: Zupanic, Eva | von Euler, Mia | Winblad, Bengt | Xu, Hong | Secnik, Juraj | Kramberger, Milica Gregoric | Religa, Dorota | Norrving, Bo | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Stroke and dementia are interrelated diseases and risk for both increases with age. Even though stroke incidence and age-standardized death rates have decreased due to prevention of stroke risk factors, increased utilization of reperfusion therapies, and other changes in healthcare, the absolute numbers are increasing due to population growth and aging. Objective: To analyze predictors of death after stroke in patients with dementia and investigate possible time and treatment trends. Methods: A national longitudinal cohort study 2007–2017 using Swedish national registries. We compared 12,629 ischemic stroke events in patients with dementia with matched 57,954 stroke …events in non-dementia controls in different aspects of patient care and mortality. Relationship between dementia status and dementia type (Alzheimer’s disease and mixed dementia, vascular dementia, other dementias) and death was analyzed using Cox regressions. Results: Differences in receiving intravenous thrombolysis between patients with and without dementia disappeared after the year 2015 (administered to 11.1% dementia versus 12.3% non-dementia patients, p  = 0.117). One year after stroke, nearly 50% dementia and 30% non-dementia patients had died. After adjustment for demographics, mobility, nursing home placement, and comorbidity index, dementia was an independent predictor of death compared with non-dementia patients (HR 1.26 [1.23–1.29]). Conclusion: Dementia before ischemic stroke is an independent predictor of death. Over time, early and delayed mortality in patients with dementia remained increased, regardless of dementia type. Patients with≤80 years with prior Alzheimer’s disease or mixed dementia had higher mortality rates after stroke compared to patients with prior vascular dementia. Show more

Keywords: Alzheimer’s disease, dementia, ischemic stroke, mixed dementia, mortality, vascular dementia

DOI: 10.3233/JAD-201459

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1253-1261, 2021

Authors: Kim, Won Jun | Noh, Jung Hyun | Han, Kyungdo | Park, Cheol-Young

Article Type: Research Article

Abstract: Background: There are few reports that evaluated the association between various types of dementia and dual oral therapy with antihyperglycemic medication. Objective: The goal of this study was to investigate the association between treatment of dual antihyperglycemic medication and dementia subclass in type 2 diabetes mellitus using the Korean National Health Insurance System. Methods: This study included 701,193 individuals with diabetes prescribed dual oral therapy between 2009 and 2012 from the Korean National Health Insurance Service Database, which were tracked until 2017. All-cause, Alzheimer’s (AD) and vascular dementia (VaD) were investigated by dual oral therapy. Adjustments …were made for age, sex, income, diabetes duration, hypertension, dyslipidemia, smoking, drinking, exercise, body mass index, glucose level, and estimated glomerular filtration rate. Results: Dual therapy with metformin (Met) + dipeptidyl peptidase-4 inhibitor (DPP-4i), Met + thiazolidinedione (TZD), and sulfonylurea (SU) + thiazolidinediones (TZD) were significantly associated with all-cause dementia (HR = 0.904, 0.804, and 0.962, respectively) and VaD (HR = 0.865, 0.725, and 0.911, respectively), compared with Met + SU. Met + DPP-4i and Met + TZD were associated with significantly lower risk of AD (HR = 0.922 and 0.812), compared with Met + SU. Dual therapy with TZD was associated with a significantly lower risk of all-cause dementia, AD, and VaD than nonusers of TZD (HR = 0.918, 0.925 and 0.859, respectively). Conclusion: Adding TZD or DPP-4i instead of SU as second-line anti-diabetic treatment may be considered for delaying or preventing dementia. Also, TZD users relative to TZD non-users on dual oral therapy were significantly associated with lower risk of various types of dementia. Show more

Keywords: Alzheimer’s disease, dementia, dipeptidyl-peptidase IV inhibitors, population, type 2 diabetes mellitus, 2, 4-thiazolidinedione

DOI: 10.3233/JAD-201535

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1263-1272, 2021

Authors: Smirni, Daniela | Oliveri, Massimiliano | Misuraca, Eliana | Catania, Angela | Vernuccio, Laura | Picciolo, Valentina | Inzerillo, Flora | Barbagallo, Mario | Cipolotti, Lisa | Turriziani, Patrizia

Article Type: Research Article

Abstract: Background: Recent studies showed that in healthy controls and in aphasic patients, inhibitory trains of repetitive transcranial magnetic stimulation (rTMS) over the right prefrontal cortex can improve phonemic fluency performance, while anodal transcranial direct current stimulation (tDCS) over the left prefrontal cortex can improve performance in naming and semantic fluency tasks. Objective: This study aimed at investigating the effects of cathodal tDCS over the left or the right dorsolateral prefrontal cortex (DLPFC) on verbal fluency tasks (VFT) in patients with mild Alzheimer’s disease (AD). Methods: Forty mild AD patients participated in the study (mean age 73.17±5.61 …years). All participants underwent cognitive baseline tasks and a VFT twice. Twenty patients randomly received cathodal tDCS to the left or the right DLPFC, and twenty patients were assigned to a control group in which only the two measures of VFT were taken, without the administration of the tDCS. Results: A significant improvement of performance on the VFT in AD patients was present after tDCS over the right DLPFC (p  = 0.001). Instead, no difference was detected between the two VFTs sessions after tDCS over the left DLPFC (p  = 0.42). Furthermore, these results cannot be related to task learning effects, since no significant difference was found between the two VFT sessions in the control group (p  = 0.73). Conclusion: These data suggest that tDCS over DLPFC can improve VFT performance in AD patients. A hypothesis is that tDCS enhances adaptive patterns of brain activity between functionally connected areas. Show more

Keywords: Dorsolateral prefrontal cortex, mild Alzheimer’s disease, transcranial direct current stimulation, verbal fluency

DOI: 10.3233/JAD-210003

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1273-1283, 2021

Authors: Lin, Yajie | Zeng, Qingze | Hu, MengJie | Peng, Guoping | Luo, Benyan | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) is an important protective factor for Alzheimer’s disease (AD), yet its mechanism has not been fully elucidated. Objective: To explore the effect of CR on resting and dynamic brain intrinsic activity in patients with mild cognitive impairment (MCI). Methods: 65 amyloid-β PET-negative (Aβ-) normal controls (NC) and 30 amyloid-β PET-positive (Aβ+) MCI patients underwent resting-state functional magnetic resonance imaging were included from Alzheimer’s Disease Neuroimaging Initiative. According to the years of education, the subjects were divided into high education group and low education group. A two-way analysis of variance was employed for …the fractional amplitude of low-frequency fluctuation (fALFF) and dynamic fALFF (dfALFF) comparisons among the four groups. Moreover, the interaction effect of neuroimaging×pathology on clinical cognitive function was tested with linear regression analysis. Results: The value of fALFF in the left prefrontal lobe was increased in Aβ+ MCI patients compared to Aβ- NC. The significant interactive effect between disease state and education (binary factor) was observed in the right parahippocampal gyrus (PHG) for fALFF, the right PHG and the right inferior parietal lobule for dfALFF. While no significant results between education (continuous factor) and brain activity was found in voxel-by-voxel analysis. For MCI patients, a significant fluorodeoxyglucose hypometabolic convergence index×right PHG dfALFF interaction was found, indicating the maintenance of executive function at higher levels of dfALFF in the right PHG. Conclusion: High CR can alleviate the impairment of hypometabolism on executive function in MCI patients, which is partially achieved by regulating the dynamic brain activity in the right PHG. Show more

Keywords: Cognitive reserve, dynamic intrinsic brain activity, mild cognitive impairment, right parahippocampal gyrus

DOI: 10.3233/JAD-201244

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1285-1294, 2021

Authors: de Oliveira, Fabricio Ferreira | Miraldo, Marjorie Câmara | de Castro-Neto, Eduardo Ferreira | de Almeida, Sandro Soares | Matas, Sandro Luiz de Andrade | Bertolucci, Paulo Henrique Ferreira | Naffah-Mazzacoratti, Maria da Graça

Article Type: Research Article

Abstract: Background: Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases. Objective: We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer’s disease (AD) and cognitively healthy people. Methods: Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-β (Aβ)42 , Aβ40 , Aβ38 , total tau, phospho-tau Thr181 , α-synuclein, ubiquitin, and neurofilament light …with neuropsychiatric features according to APOE ɛ 4 carrier status. Results: Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOE ɛ 4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOE ɛ 4 carriers) and 27 controls (78.48±8.7 years old, four APOE ɛ 4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOE ɛ 4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis. Conclusion: Biomarker ratios were superior to Aβ and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOE ɛ 4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB. Show more

Keywords: Alzheimer’s disease, APOE, behavioral symptoms, biomarkers, cerebrospinal fluid, dementia, Lewy body dementia, neuropsychiatry

DOI: 10.3233/JAD-210272

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1295-1309, 2021