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

Authors: Bernstein, John P.K. | Dorociak, Katherine E. | Mattek, Nora | Leese, Mira | Beattie, Zachary T. | Kaye, Jeffrey A. | Hughes, Adriana

Article Type: Research Article

Abstract: Background: Computer use is a cognitively complex instrumental activity of daily living (IADL) that has been linked to cognitive functioning in older adulthood, yet little work has explored its capacity to detect incident mild cognitive impairment (MCI). Objective: To examine whether routine home computer use (general computer use as well as use of specific applications) could effectively discriminate between older adults with and without MCI, as well as explore associations between use of common computer applications and cognitive domains known to be important for IADL performance. Methods: A total of 60 community-dwelling older adults (39 cognitively …healthy, 21 with MCI) completed a neuropsychological evaluation at study baseline and subsequently had their routine home computer use behaviors passively recorded for three months. Results: Compared to those with MCI, cognitively healthy participants spent more time using the computer, had a greater number of computer sessions, and had an earlier mean time of first daily computer session. They also spent more time using email and word processing applications, and used email, search, and word processing applications on a greater number of days. Better performance in several cognitive domains, but in particular memory and language, was associated with greater frequency of browser, word processing, search, and game application use. Conclusion: Computer and application use are useful in identifying older adults with MCI. Longitudinal studies are needed to determine whether decreases in overall computer use and specific computer application use are predictors of incident cognitive decline. Show more

Keywords: Aging, computer use, mild cognitive impairment, technology

DOI: 10.3233/JAD-210049

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1053-1064, 2021

Authors: Mizuno, Akiko | Karim, Helmet T. | Ly, Maria J. | Cohen, Ann D. | Lopresti, Brian J. | Mathis, Chester A. | Klunk, William E. | Aizenstein, Howard J. | Snitz, Beth E.

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer’s disease. Elevated amyloid-β (Aβ) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aβ is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates. Objective: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aβ, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations. Methods: We …measured brain activation during the “face-name” memory-encoding fMRI task and Aβ deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n = 63, mean age 73.1 ± 7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aβ, and interactions with education. Results: Activation was not directly associated with SCD symptoms or Aβ. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education. Conclusion: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve. Show more

Keywords: Amyloid, cognitive reserve, functional MRI, PiB-PET, preclinical dementia, subjective cognitive decline

DOI: 10.3233/JAD-201087

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1065-1078, 2021

Authors: Michaelian, Johannes C. | Duffy, Shantel L. | Mowszowski, Loren | Guastella, Adam J. | McCade, Donna | McKinnon, Andrew C. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Older adults living with amnestic mild cognitive impairment (aMCI) not only demonstrate impairments in Theory of Mind (ToM), relative to adults with non-amnestic MCI (naMCI), but are also at a higher risk of developing dementia. Objective: Our primary objective was to ascertain whether default mode network (DMN) functional connectivity was differentially associated with ToM abilities between MCI subgroups. Methods: Using functional magnetic resonance imaging, we investigated alterations in resting-state functional connectivity within the brain’s DMN in a sample of 43 older adults with aMCI (n  = 19) and naMCI (n  = 24), previously reported to demonstrate poorer …ToM abilities. Results: Compared to naMCI, the aMCI subgroup revealed a significant association between poorer ToM performance and reduced functional connectivity between the bilateral temporal pole (TempP) and the left lateral temporal cortex (LTC) (LTC_L-TempP_L : b  = –0.06, t(33) = –3.53, p  = 0.02; LTC_L-TempP_R : b  = –0.07,t(33) = –3.20, p  = 0.03); between the right TempP and the dorsal medial prefrontal cortex (dMPFC) (b  = –0.04, t(33) = –3.02, p  = 0.03) and between the left and right TempP (b  = –0.05, t(33) = –3.26, p  = 0.03). In the naMCI subgroup, the opposite relationship was present between the bilateral TempP and the left LTC (Combined correlation: r  = –0.47, p  = 0.02), however, not between the right TempP and the dMPFC (r  = –0.14, p  = 0.51) or the left and right TempP (r  = –0.31, p  = 0.14). Conclusion: Our findings suggest that alterations in functional connectivity within the DMN involving temporal and frontal lobe regions are associated with ToM deficits in aMCI. Show more

Keywords: Amnestic mild cognitive impairment, default mode network, functional connectivity, functional magnetic resonance imaging, theory of mind

DOI: 10.3233/JAD-201284

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1079-1091, 2021

Authors: Sakurai, Keita | Kaneda, Daita | Inui, Shohei | Uchida, Yuto | Morimoto, Satoru | Nihashi, Takashi | Kato, Takashi | Ito, Kengo | Hashizume, Yoshio

Article Type: Research Article

Abstract: Background: The differentiation of Alzheimer’s disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. Objective: The purpose of this study is …to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. Methods: Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. Results: Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). Conclusion: Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice. Show more

Keywords: Alzheimer’s disease, argyrophilic grain disease, hippocampal angle, limbic tauopathy, magnetic resonance imaging, senile dementia of the neurofibrillary tangle type, ventricular enlargement

DOI: 10.3233/JAD-210043

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1093-1102, 2021

Authors: Halminen, Olli | Vesikansa, Aino | Mehtälä, Juha | Hörhammer, Iiris | Mikkola, Teija | Virta, Lauri J. | Ylisaukko-oja, Tero | Linna, Miika

Article Type: Research Article

Abstract: Background: Dementia is one of the strongest predictors of admission to a 24-hour care facility among older people, and 24-hour care is the major cost of Alzheimer’s disease (AD). Objective: The aim of this study was to evaluate the association of early start of anti-dementia medication and other predisposing factors with 2-year risk of transition to 24-hour care in the nationwide cohort of Finnish AD patients. Methods: This was a retrospective, non-interventional study based on individual-level data from Finnish national health and social care registers. The incident cohort included 7,454 AD patients (ICD-10, G30) comprised of …two subgroups: those living unassisted at home (n  = 5,002), and those receiving professional home care (n  = 2,452). The primary outcome was admission to a 24-hour care facility. Exploratory variables were early versus late anti-dementia medication start, sociodemographic variables, care intensity level, and comorbidities. Results: Early anti-dementia medication reduced the risk of admission to 24-hour care both in patients living unassisted at home, with a hazard ratio (HR) of 0.58 (p  < 0.001), and those receiving professional home care (HR, 0.84; p  = 0.039). Being unmarried (HR, 1.69; p  < 0.001), having an informal caregiver (HR, 1.69; p  = 0.003), or having a diagnosis of additional neurological disorder (HR, 1.68; p  = 0.006) or hip fracture (HR, 1.61; p  = 0.004) were associated with higher risk of admission to 24-hour care in patients living unassisted at home. Conclusion: To support living at home, early start of anti-dementia medication should be a high priority in newly diagnosed AD patients. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, dementia, Finland, healthcare, institutionalization, memantine, nursing homes, register

DOI: 10.3233/JAD-201502

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1103-1115, 2021

Authors: Nerg, Ossi | Junkkari, Antti | Hallikainen, Ilona | Rauramaa, Tuomas | Luikku, Antti | Hiltunen, Mikko | Jääskeläinen, Juha E. | Leinonen, Ville | Hänninen, Tuomo | Koivisto, Anne

Article Type: Research Article

Abstract: Background: The usefulness of CERAD Neuropsychological Battery for describing the cognitive impairment in idiopathic normal pressure hydrocephalus (iNPH) is unknown. Objective: To compare the cognitive profile of patients with iNPH to patients with mild Alzheimer’s disease (AD) and age-matched cognitively healthy individuals by using the CERAD-NB. Methods: We studied CERAD-NB subtest results, including the Mini-Mental State Examination (MMSE), between 199 patients with probable iNPH, 236 patients with mild AD, and 309 people with normal cognition, using age, education, and gender adjusted multivariate linear regression model. In addition, the effects of AD-related brain pathology detected in frontal …cortical brain biopsies in iNPH patients’ cognitive profiles were examined. Results: The iNPH patients performed worse than cognitively healthy people in all CERAD-NB subtests. Despite similar performances in the MMSE, AD patients outperformed iNPH patients in Verbal Fluency (p  = 0.016) and Clock Drawing (p  < 0.001) tests. However, iNPH patients outperformed AD patients in the Boston Naming Test and Word List Recall and Recognition (p  < 0.001). AD-related pathology in brain biopsies did not correlate with the CERAD-NB results. Conclusion: At the time of the iNPH diagnosis, cognitive performances differed from cognitively healthy people in all CERAD-NB subtests. When the iNPH and AD patients’ results were compared, the iNPH patients performed worse in Verbal Fluency and Clock Drawing tests while the AD group had more pronounced episodic memory dysfunctions. This study demonstrates significant differences in the CERAD-NB subtests between cognitive profiles of iNPH and AD patients. These differences are not captured by the MMSE alone. Show more

Keywords: Alzheimer’s disease, CERAD-NB, Mini-Mental Status Examination, neuropsychological test, normal pressure hydrocephalus

DOI: 10.3233/JAD-201363

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1117-1130, 2021

Authors: Gottesman, Reena T. | Kociolek, Anton | Fernandez, Kayri | Cosentino, Stephanie | Devanand, D.P. | Stern, Yaakov | Gu, Yian

Article Type: Research Article

Abstract: Background: Psychotic symptoms are an important and increasingly recognized aspect of Alzheimer’s disease (AD). They have been shown to contribute to faster disease progression in clinic-based, demographically homogenous samples with high educational attainment. Objective: We studied the association between baseline psychotic symptoms and disease progression among individuals with incident AD or ‘at risk’ of developing AD, from a demographically heterogenous, community-based cohort with minimal educational attainment. Methods: 212 participants received the Columbia University Scale of Psychopathology in Alzheimer’s Disease scale. Participants had psychotic symptoms with any of: visual illusions, delusions, hallucinations, or agitation/aggression. Disease progression was …measured yearly and defined by meeting cognitive (≤10 on the Folstein MMSE) or functional endpoints (≥10 on the Blessed Dementia Rating Scale or ≥4 on the Dependence Scale). Results: The mean age was 85 years old. The cohort was 78.3% female, 75.9% Hispanic, and had a mean 6.96 years of education. Within the follow-up period (mean: 3.69 years), 24 met the cognitive endpoint, 59 met the functional endpoint, and 132 met the cutoff for dependence. The presence of at least one psychotic symptom was initially associated with an increased risk of reaching the functional endpoint (HR 3.12, 95% CI 1.67–5.86, p  < 0.001) and the endpoint of dependence (HR = 1.498, 95% CI 1.05–2.13, p  = 0.03). However, these associations were attenuated and non-significant when adjusted for baseline functional status. Psychotic symptoms were not associated with the cognitive endpoint. Conclusion: Psychotic symptoms may predict functional decline in patients of non-Caucasian ethnicity and with lower educational attainment. Show more

Keywords: Alzheimer’s disease, ethnic groups, neurobehavioral manifestations, prognosis

DOI: 10.3233/JAD-200729

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1131-1139, 2021

Authors: Xu, Lujie | Li, Tao | Xiong, Lingchuan | Wang, Xiao | Ismail, Zahinoor | Fukuda, Masami | Sun, Zhiyu | Wang, Jing | Gauthier, Serge | Yu, Xin | Wang, Huali

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) has been proposed as an early manifestation of dementia. The Mild Behavioral Impairment Checklist (MBI-C) may help identify MBI in prodromal and preclinical dementia. Objective: The study aimed to evaluate the reliability and validity of the Chinese version of MBI-C in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD), and to explore the structure of the five factors of the MBI-C in Chinese culture. Methods: Sixty dyads of MCI and mild AD (MCI, n  = 33; mild AD, n  = 35) were recruited. The informants completed the MBI-C and Neuropsychiatric Inventory Questionnaire …(NPI-Q) and were interviewed for clinician rating of the NPI. The Cronbach’s coefficient was used to measure the structural reliability of the MBI-C. The criterion-validity was evaluated with the correlation coefficient between the MBI-C and the total scores of NPI-Q and NPI. Exploratory factor analysis was conducted to investigate the structure of the MBI-C. Results: The Cronbach’s α coefficient was 0.895. The MBI-C total score was positively correlated with all five domains (r  = 0.577∼0.840). The total score of MBI-C was significantly correlated with the total scores of NPI-Q (r  = 0.714) and NPI (r  = 0.749). Similarly, the five domain scores of MBI-C were significantly correlated with the factor and total scores of NPI-Q (r  = 0.312∼0.673) and NPI (r  = 0.389∼0.673). The components of each factor in Chinese version of MBI-C were slightly different from those of the a priori defined domains (χ 2  = 1818.202, df = 496, p  < 0.001). Conclusion: The Chinese version of MBI-C has good reliability and validity, and can be used to evaluate the psychological and behavioral changes in MCI and mild AD. Show more

Keywords: Mild behavioral impairment, Mild Behavioral Impairment Checklist (MBI-C), mild cognitive impairment, reliability, validity

DOI: 10.3233/JAD-210098

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1141-1149, 2021

Authors: Beuckmann, Carsten T. | Suzuki, Hiroyuki | Musiek, Erik S. | Ueno, Takashi | Sato, Toshitaka | Bando, Masahiro | Osada, Yoshihide | Moline, Margaret

Article Type: Research Article

Abstract: Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running …wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances. Show more

Keywords: Alzheimer’s disease, animal models, dual orexin receptor antagonist, E2006, in vivo , irregular sleep-wake rhythm disorder, lemborexant, mouse, orexin, running wheel, sleep

DOI: 10.3233/JAD-201054

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1151-1167, 2021

Authors: Feldman, Robin

Article Type: Research Article

Abstract: Background: US direct-to-consumer advertising spending for medicine has soared in recent decades. Advertising has been shown to impact drug utilization. Most Alzheimer’s disease patients are above age 65 and may take a range of prescription medications for various disease states. Objective: To investigate how direct-to-consumer advertising is associated with the drug utilization of patients ≥65 years old. Methods: Using advertising expenditure data and Medicare Part D drug purchase claims, we performed regression analyses for each of the highest-spending drugs and age group, with cumulative monthly spending as the predictor variable and drug utilization as the response …variable. For each drug, we ran a second set of regression analyses to determine if the spending-utilization correlation showed a significant difference between the two patient age groups (older than 65, younger than 65). Results: For all 14 drugs in our study, advertising spending is positively correlated with utilization (p  < 0.01) in both age groups. For seven of the 14 drugs studied, the difference in the utilization of patients older than 65 and the utilization of patients younger than 65 is statistically significant at a p  < 0.01 level. The 65-and-older age bracket exhibits significantly greater utilization for all seven of these drugs. Conclusion: We find televised advertising for certain drugs to be associated with significantly stronger drug utilization among seniors, as compared to younger patients. Alzheimer’s disease physicians should be aware of this result, in light of the medications that patients may take for other disease states, particularly mood and mental health medications. Show more

Keywords: Aged, direct-to-consumer advertising, drug utilization, health services for the aged, prescription drugs, public health, television

DOI: 10.3233/JAD-210294

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1169-1179, 2021

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

Authors: Nasrun, Martina Wiwie S. | Kusumaningrum, Profitasari | Redayani, Petrin | Lahino, Hasya Layalia | Mardhiyah, Fithriani Salma | Basfiansa, Amadeo D. | Nadila, Nindya

Article Type: Research Article

Abstract: Background: Caregivers, as one of the most important roles in caring for a person with dementia, have a challenging task. Therefore, maintaining the quality of life (QoL) of caregivers is an integral part of dementia care. Objective: To explore the relationship between the QoL of people with dementia and their caregivers in Indonesia. Methods: This is a cross-sectional study using binary correlations to analyze the relationship between people with dementia and caregivers’ QoL. Conducted in Cipto Mangunkusumo Hospital in Jakarta, the subjects were 42 people diagnosed with dementia according to the PPDGJ-III (adapted from the ICD …10) and 42 primary caregivers with at least 6 hours duration of caregiving per day. The QoL of people with dementia was measured by EuroQol-5D and VAS EQ-5D, while severity of dementia was measured by MMSE. Caregivers underwent an interview using WHO Quality of Life Instrument (WHOQOL-BREF) and NPI. Results: Most caregivers were women, aged 40–70 years old. The study found caregivers’ QoL environmental domain strongly correlated with people with dementia’s QoL (r  = 0.839). Severity of dementia had a strong correlation with caregivers’ QoL physical domain (r  = 0.946). Age, duration of caregiving per day, period of care provided by caregivers, and caregiver’s distress had a strong correlation with caregiver QoL for specific domains. Conclusion: There was a strong correlation between people with dementia’s QoL and caregiver QoL, so in managing dementia, clinicians should consider caregivers’ wellbeing as an essential part significantly affecting the quality of elderly care improvement. Show more

Keywords: Caregivers, dementia, Indonesia, quality of life

DOI: 10.3233/JAD-201550

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1311-1320, 2021

Authors: Bertrand, Elodie | van Duinkerken, Eelco | Laks, Jerson | Dourado, Marcia Cristina Nascimento | Bernardes, Gabriel | Landeira-Fernandez, Jesus | Mograbi, Daniel C.

Article Type: Research Article

Abstract: Background: Unawareness of disease is a common feature of Alzheimer’s disease (AD), but few studies explored its neural correlates. Additionally, neural correlates according to the object of awareness are unexplored. Objective: To investigate structural brain correlates in relation to different objects of awareness. Methods: 27 people with AD underwent MRI scanning on a 3T Siemens Prisma. T1-MPRAGE was used to investigate cortical thickness and white matter microstructure was defined by DTI as fractional anisotropy, mean, axial, and radial diffusivity. Preprocessing used FreeSurfer6.0, ExploreDTI, and FSL-TBSS. Awareness of disease, cognitive deficits, emotional state, relationships, and functional capacity …were assessed with the short version of the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia. Voxel-wise correlations between brain structure and awareness were determined by FSL-PALM. Analyses were corrected for multiple comparisons using Threshold Free Cluster Enhancement and FWE. Results: Lower left hemisphere cortical thickness was related to poorer disease awareness uncorrected and corrected for age, sex, and MMSE. In the uncorrected model, mainly right-sided, but also left temporal lower cortical thickness was related to decreased awareness of cognitive deficits. Correcting for age, sex, and MMSE eliminated correlations for the right hemisphere, but extensive correlations in the left hemisphere remained. For white matter integrity, higher right hemisphere MD was related to lower cognitive awareness deficits, and lower FA was related to lower functional capacity awareness. Conclusion: Findings suggest that extensive regions of the brain are linked to self-awareness, with particular frontal and temporal alterations leading to unawareness, in agreement with theoretical models indicating executive and mnemonic forms of anosognosia in AD. Show more

Keywords: Alzheimer’s disease, anosognosia, awareness, diffusion tensor imaging MRI, magnetic resonance imaging

DOI: 10.3233/JAD-201246

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1321-1330, 2021

Authors: Wang, Ya-Yu | Ge, Yi-Jun | Tan, Chen-Chen | Cao, Xi-Peng | Tan, Lan | Xu, Wei

Article Type: Research Article

Abstract: Background: The apolipoprotein E epsilon 4 (APOE4 ) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). Its carriage percentage in non-demented population varies across geographic regions and ethnic groups. Objective: To estimate the proportion of APOE4 (2/4, 3/4, or 4/4) carriers in non-demented community-dwellers. Methods: PubMed, EMBASE, and China National Knowledge Infrastructure were searched from inception to April 20, 2020. Community-based studies that reported APOE polymorphisms with a sample of≥500 non-demented participants were included. Random-effects models were used to pool the results. Meta-regression and subgroup analyses were performed to test the …source of heterogeneity and stratified effects. Age-standardized pooled proportion estimates (ASPPE) were calculated by direct standardization method. Results: A total of 121 studies were included, with a pooled sample of  389,000 community-dwellers from 38 countries. The global average proportion of APOE4 carriers was 23.9% (age-standardized proportion: 26.3%; 2.1% for APOE4/4 , 20.6% for APOE3/4 and 2.3% for APOE2/4 ), and varied significantly with geographical regions (from 19.3% to 30.0%) and ethnic groups (from 19.1% to 37.5%). The proportion was highest in Africa, followed by Europe, North America, Oceania, and lowest in South America and Asia (p  < 0.0001). With respect to ethnicity, it was highest in Africans, followed by Caucasians, and was lowest in Hispanics/Latinos and Chinese (p  < 0.0001). Conclusion: APOE4 carriers are common in communities, especially in Africans and Caucasians. Developing precision medicine strategies in this specific high-risk population is highly warranted in the future. Show more

Keywords: Alzheimer’s disease, APOE4 , proportion, worldwide

DOI: 10.3233/JAD-201606

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1331-1339, 2021

Article Type: Correction

DOI: 10.3233/JAD-219004

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1341-1341, 2021

Article Type: Correction

DOI: 10.3233/JAD-219005

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1343-1343, 2021