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

Authors: Schmidt, Guilherme J. | Boechat, Yolanda Eliza Moreira | van Duinkerken, Eelco | Schmidt, Juliana J. | Moreira, Tayssa B. | Nicaretta, Denise H. | Schmidt, Sergio L.

Article Type: Research Article

Abstract: Background: Scales for cognitive deterioration usually depend on education level. Objective: We aimed to study the clinical utility of a culture-free Go/No-Go task in a multi-ethnic cohort with low education level. Methods: Sixty-four participants with less than 4 years of formal education were included and divided on the basis of their Clinical-Dementia-Rate scores (CDR) into cognitively unimpaired (CDR = 0), mild cognitive impairment (MCI; CDR = 0.5), and early Alzheimer’s disease (AD, CDR = 1). All underwent a 90-s Continuous Visual Attention Test. This test consisted of a 90-s Go/No-go task with 72 (80%) targets and 18 (20%) non-targets. For each participant, …reaction times and intraindividual variability of reaction times of all correct target responses, as well as the number of omission and commission errors were evaluated. Coefficient of variability was calculated for each participant by dividing the standard deviation of the reaction times by the mean reaction time. A MANCOVA was performed to examine between-group differences using age and sex as covariates. Discriminate analysis was performed to find the most reliable test-variable to discriminate the three groups. Results: Commission error, intraindividual variability of reaction time, and coefficient of variability progressively worsened with increasing CDR level. Discriminant analysis demonstrated that coefficient of variability was the best discriminant factor, followed by intraindividual variability of reaction time and commission error. Conclusion: The Go/No-Go task was able to discriminate people with MCI or early AD from controls in the setting of illiteracy. Show more

Keywords: Attention, cognitive dysfunction, dementia, neuropsychology, reaction time

DOI: 10.3233/JAD-200881

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Shams, Mana | Martola, Juha | Charidimou, Andreas | Granberg, Tobias | Ferreira, Daniel | Westman, Eric | Wintermark, Max | Iv, Michael | Larvie, Mykol | Kristoffersen Wiberg, Maria | Kaijser, Magnus | Forsgard, Niklas | Zetterberg, Henrik | Wahlund, Lars-Olof | Shams, Sara

Article Type: Research Article

Abstract: Background: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. Objective: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. Methods: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) …42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. Results: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42 , T-tau, P-tau, and CSF/serum albumin ratios (p  < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOE ɛ 4 carriers. Conclusion: CSF iron levels are elevated with cerebral microbleeds in APOE ɛ 4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognitive aging, dementia, magnetic resonance imaging

DOI: 10.3233/JAD-200656

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

Authors: Clare, Linda | Martyr, Anthony | Henderson, Catherine | Gamble, Laura | Matthews, Fiona E. | Quinn, Catherine | Nelis, Sharon M. | Rusted, Jennifer | Thom, Jeanette | Knapp, Martin | Hart, Nicola | Victor, Christina

Article Type: Research Article

Abstract: Background: A significant proportion of people with dementia live alone, but little is known about their specific needs. Objective: To understand the profile of people living alone with mild-to-moderate dementia in the UK and identify any systematic differences associated with living situation. Methods: We analyzed cross-sectional data from 1,541 people with mild-to-moderate dementia and 1,277 caregivers participating in the IDEAL cohort at the first wave of assessment. Results: There were 1,256 (81.5%) people with dementia living with others and 285 (18.5%) living alone, of whom 51 (3% of whole sample) reported little or no …informal support. There were relatively few differences associated with living situation and odds ratios were generally small. People living alone were older on average, and more likely to be female, than those living with others. Those living alone were more likely to have higher cognitive ability and self-reported functional ability, and more social contact with those from other households. They were also lonelier, expressed less satisfaction with life, and used home care services and equipment more. There were no differences in symptoms, mood, quality of life, or well-being. Conclusion: The findings support the view that it is possible to ‘live well’ with mild-to-moderate dementia while living alone, given appropriate support, including home care and equipment. Nevertheless, it is important to consider how those living alone may be supported to have a more satisfactory experience, and how health and social care services can best respond to their needs. Show more

Keywords: Aids and adaptations, Alzheimer’s disease, service use, social capitals, assets and resources, vascular dementia

DOI: 10.3233/JAD-200638

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

Authors: Bartels, Claudia | Kögel, Anna | Schweda, Mark | Wiltfang, Jens | Pentzek, Michael | Schicktanz, Silke | Schneider, Anja

Article Type: Research Article

Abstract: Background: The National Institute of Aging and Alzheimer’s Association’s diagnostic recommendations for preclinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. Objective: We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. Methods: We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals …and memory clinics) in Germany. Results: From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42 , tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p ≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p  = 0.006), given that all CSF biomarkers were in the pathological range. Conclusion: Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed. Show more

Keywords: Alzheimer’s disease, biomarker, mild cognitive impairment, prediction, questionnaires, subjective cognitive decline, surveys

DOI: 10.3233/JAD-200794

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

Authors: Tan, Meng-Shan | Yang, Yu-Xiang | Wang, Hui-Fu | Xu, Wei | Tan, Chen-Chen | Zuo, Chuan-Tao | Dong, Qiang | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer’s disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms. Objective: Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status. Methods: We included 372 nondemented elderly from the Alzheimer’s Disease Neuroimaging Initiative cohort. …All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels. Results: Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42 , APOE ɛ 4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels. Conclusion: Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE, biomarker, cerebrospinal fluid, Mini-Mental State Examination, PET, tau

DOI: 10.3233/JAD-200124

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

Authors: Zhang, Zhihua | Sheng, Hongxia | Liao, Li | Xu, Chen | Zhang, Ang | Yang, Yang | Zhao, Long | Duan, Lian | Chen, Hu | Zhang, Bin

Article Type: Research Article

Abstract: Background: Mesenchymal stem cells-conditioned medium (MSC-CM) provides a promising cell-free therapy for Alzheimer’s disease (AD) mainly due to the paracrine of MSCs, but the precise mechanisms remain unclear. Studies suggests that mitochondrial dysfunction precedes the accumulation of amyloid-β plaques and neurofibrillary tangles, and involves in the onset and development of AD. Objective: In the present study, we evaluated the protective effects and explored the related-mitochondrial mechanisms of human umbilical cord derived MSC-CM (hucMSC-CM) in an AD model in vitro . Methods: To this end, an AD cellular model was firstly established by okadaic acid (OA)-treated SH-SY5Y …cells, and then treated by hucMSC-CM to assess the oxidative stress, mitochondrial function, apoptosis, AD-related genes, and signaling pathways. Results: hucMSC-CM significantly deceased tau phosphorylated at Thr181 (p181 -tau) level, which was increased in AD. hucMSC-CM also alleviated intracellular and mitochondrial oxidative stress in OA-treated SH-SY5Y cells. In addition, hucMSC-CM suppressed apoptosis and improved mitochondrial function in OA-treated SH-SY5Y cells. Flow cytometric analysis indicated that hucMSC-CM exerted the protective effects relying on or partly extracellular vesicle (EV) mitochondrial transfer from hucMSCs to OA-treated SH-SY5Y cells. Moreover, RNA sequencing data further demonstrated that hucMSC-CM regulated many AD-related genes, signaling pathways and mitochondrial function. Conclusion: These results indicated that MSC-CM or MSC-EVs containing abundant mitochondria may provide a novel potential therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, apoptosis, mesenchymal stem cell-conditioned medium, mitochondrial dysfunction, mitochondrial transfer

DOI: 10.3233/JAD-200686

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Ghilain, Matthieu | Hobeika, Lise | Lesaffre, Micheline | Schiaratura, Loris | Singh, Ashmita | Six, Joren | Huvent-Grelle, Dominique | Puisieux, François | Samson, Séverine

Article Type: Research Article

Abstract: Background: Music-based interventions appear to be efficient approaches to improve emotional, social, and cognitive functioning of patients with neurodegenerative diseases. Objective: Because benefits seem to increase with patient’s motor involvement, we studied sensorimotor synchronization (SMS) abilities of patients with cognitive impairments (Alzheimer’s disease, vascular and mixed dementia) and of patients with no evidence of cognitive impairments. More specifically, we compared the impact of a live performance by a musician to a video recording on SMS. Methods: SMS to a metronomic or a musical stimulus was assessed while patients watched a live musician or his pre-recorded video. …Results: SMS to a metronome was better than to music but this effect was modulated by the social context. While SMS to a metronome was better when facing a video than a live performance, there was no impact of social context on SMS to music. No group differences of SMS were found. Conclusion: The decrease in SMS to a metronome in a live performance may be due to social pressure. Such a pressure might be removed in pleasant social activities, like moving with music in a group, explaining the lack of effect on SMS to music. We found no performance differences in groups, suggesting relatively spared SMS in cognitively impaired patients. By showing that it is possible to encourage patients to synchronize with others, even when facing a video, our results indicate that SMS can be used as a relevant predictor in clinical trials and open up promising therapeutic options for isolated patients. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, dementia, motor activity, music therapy, social interaction

DOI: 10.3233/JAD-200521

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

Authors: Gkioka, Mara | Schneider, Julia | Kruse, Andreas | Tsolaki, Magda | Moraitou, Despina | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: People with dementia (PwD) are frequently admitted to hospital settings. The lack of proper dementia knowledge, poor communication skills, negative attitudes toward dementia, and lack of confidence affects the quality of care, thus development of dementia trainings has increased. Nevertheless, literature regarding the effectiveness of training implementation is limited. Objective: The aim of this narrative synthesis is to 1) identify the characteristics of training programs and 2) explore the effectiveness of these training programs in everyday clinical practice. Methods: A systematic search in PubMed, PsycINFO, CINAHL, and Cochrane was conducted, including qualitative and quantitative peer-reviewed …studies. Holton’s evaluation model with its three outcome levels (learning, individual performance, and organizational results) was adopted. 14 studies were included. Results: The synthesis of the results was divided into two parts: 1) to describe the characteristics and content of trainings 2) to evaluate the effectiveness of training programs according to the three outcome levels of Holton’s model, taking into consideration its construct domains: ability, motivation, and environment. Learning outcomes were assessed in all selected studies: 13 studies observed changes in individual performance, four studies reported changes within the organizational level, and only five showed sustainable changes over time. Conclusion: Person-centered care (PCC) approaches, interactive and varied teaching methods, supporting conditions like champions, action plans, and setting care policies, are all characteristics of effective trainings. Successful programs should be sustainable over time, demonstrating positive outcomes across the organization. Based on current findings, there is a lack of adequate evaluation with regard to training programs on the organizational level. Show more

Keywords: Alzheimer’s disease, education, health facilities, literature synthesis, personnel, workforce development

DOI: 10.3233/JAD-200741

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

Authors: Liu, Kathy Y. | Costello, Harry | Reeves, Suzanne | Howard, Robert | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Agitation in Alzheimer’s disease (AD) has been hypothesized to be an expression of anxiety, but whether anxiety early in the course of dementia could be a risk factor for developing later agitation is unknown. Objective: We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to examine the longitudinal relationship between anxiety and incident agitation in individuals with a diagnosis of AD at baseline or during follow-up. Methods: Longitudinal neuropsychiatric symptom data from AD individuals who were agitation-free at study baseline (N  = 272) were analyzed using mixed effects regression models to test the longitudinal relationship between …baseline and incident anxiety with incident agitation. Results: Anxiety at baseline was not associated with subsequent agitation, but there was a positive linear relationship between incident anxiety and agitation over the study duration. Baseline apathy and delusions were consistently associated with subsequent agitation and greater disease severity and illness duration also appeared to be risk factors for agitation. Conclusion: Our findings support the concept that anxiety and agitation are likely to be distinct rather than equivalent constructs in mild-moderate AD. Future longitudinal cohort studies are needed to replicate these findings and further characterize potential risk factors for agitation, such as apathy and delusions. Show more

Keywords: Agitation, Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, anxiety, apathy, delusions

DOI: 10.3233/JAD-200516

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Hallab, Asma | Lange, Catharina | Apostolova, Ivayla | Özden, Cansu | Gonzalez-Escamilla, Gabriel | Klutmann, Susanne | Brenner, Winfried | Grothe, Michel J. | Buchert, Ralph | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Research in rodents identified specific neuron populations encoding information for spatial navigation with particularly high density in the medial part of the entorhinal cortex (ERC), which may be homologous with Brodmann area 34 (BA34) in the human brain. Objective: The aim of this study was to test whether impaired spatial navigation frequently occurring in mild cognitive impairment (MCI) is specifically associated with neurodegeneration in BA34. Methods: The study included baseline data of MCI patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative with high-resolution structural MRI, brain FDG PET, and complete visuospatial ability scores of the …Everyday Cognition test (VS-ECog) within 30 days of PET. A standard mask of BA34 predefined in MNI space was mapped to individual native space to determine grey matter volume and metabolic activity in BA34 on MRI and on (partial volume corrected) FDG PET, respectively. The association of the VS-ECog sum score with grey matter volume and metabolic activity in BA34, APOE4 carrier status, age, education, and global cognition (ADAS-cog-13 score) was tested by linear regression. BA28, which constitutes the lateral part of the ERC, was used as control region. Results: The eligibility criteria led to inclusion of 379 MCI subjects. The VS-ECog sum score was negatively correlated with grey matter volume in BA34 (β= –0.229, p  = 0.022) and age (β= –0.124, p  = 0.036), and was positively correlated with ADAS-cog-13 (β= 0.175, p  = 0.003). None of the other predictor variables contributed significantly. Conclusion: Impairment of spatial navigation in MCI is weakly associated with BA34 atrophy. Show more

Keywords: Entorhinal cortex, 18F-fluorodeoxyglucose, grid cells, magnetic resonance imaging, mild cognitive impairment, positron emission tomography, spatial navigation, volumetry

DOI: 10.3233/JAD-200520

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

Authors: Juárez-Cedillo, Teresa | Gutiérrez-Gutiérrez, Lidia | Sánchez-Hurtado, Luis Alejandro | Martínez-Rodríguez, Nancy | Juarez-Cedillo, Enrique

Article Type: Research Article

Abstract: Background: Dementia is a persistent, progressive state of cognitive decline against which pharmacological intervention has a modest efficacy, reducing behavioral but not cognitive symptoms. Therefore, different non-pharmacological therapies have been developed; the most scientifically recognized are cognitive therapies that have improved cognitive function and daily life activities. Objective: To evaluate the effectiveness of a multicomponent cognitive stimulation therapy (SADEM) on cognitive and behavioral function and daily life activities in patients with mild stage dementia. Methods: Controlled clinical trial with pre- and post-intervention (12 months) and follow-up (24 months after) evaluations. Participants (67) diagnosed with mild dementia …were randomly assigned to intervention group (n  = 39) or control group (n  = 28). The intervention took place throughout one year and consisted of two weekly 90-minute sessions and one more a year after a monthly follow-up. Instruments were used to evaluate outcomes in cognitive, behavioral, and affective domains. Results: The results showed statistically significant differences, with improvement in the cognitive outcomes and the Dementia Index post-intervention (p  = 0.01). No progression of the disease was observed at the end of the study. Conclusion: The multicomponent intervention tested had positive effects on cognitive and behavioral functions and daily life activities in people with mild stage dementia, delaying progression for at least two years. Show more

Keywords: Cognitive stimulation therapy, dementia, functional cognition, multicomponent intervention, music therapy, SADEM

DOI: 10.3233/JAD-200574

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

Authors: Fields, Taylor N. | Mueller, Kimberly D. | Koscik, Rebecca L. | Johnson, Sterling C. | Okonkwo, Ozioma C. | Litovsky, Ruth Y.

Article Type: Research Article

Abstract: Background: Growing evidence suggests hearing loss is a risk factor for mild cognitive impairment and dementia, but few studies have examined its relationship to sub-clinical cognitive outcomes. Objective: To investigate the effect of self-reported hearing loss on longitudinal cognitive function in a risk-enriched cohort of clinically-unimpaired, late middle-aged adults. Methods: 579 participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) were included. Hearing status was determined via self-reported history of diagnosed hearing loss. Each participant with self-reported hearing loss was age- and sex-matched to two participants who never reported hearing loss using nearest-neighbor matching. Linear mixed-effects …models were used to examine associations between self-reported hearing loss and age-related cognitive trajectories with covariates of sex, literacy, and ethnicity, person-level random intercepts and age-related slopes. Cognitive outcomes encompassed measures of speed and flexibility, visuospatial memory, and verbal fluency. Results: Participants with self-reported hearing loss exhibited significantly poorer performance on a speed and flexibility factor score and single test of psychomotor speed and executive function, relative to participants who never reported hearing loss. There was no association between self-reported hearing loss and visuospatial memory or verbal fluency. Longitudinally, self-reported hearing loss was associated with less rapid decline in speed and flexibility and no difference in rate of decline for any other cognitive measure. Conclusion: Self-reported hearing loss was associated with poorer speed and flexibility but not with accelerated decline in any domain studied, contrary to previous findings. Further studies involving behavioral auditory measures in this cohort would clarify the robustness of these findings. Show more

Keywords: Alzheimer’s disease, cognition, cognitive impairment, executive function, hearing, hearing loss, longitudinal studies

DOI: 10.3233/JAD-200701

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Crocco, Elizabeth | Curiel-Cid, Rosie E. | Kitaigorodsky, Marcela | González-Jiménez, Christian J. | Zheng, Diane | Duara, Ranjan | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) is an increasingly utilized cognitive stress test designed to identify early cognitive changes associated with incipient neurodegenerative disease. Objective: To examine previously derived cut-points for cognitively unimpaired older adults that were suggestive of performance impairment on multiple subscales of the LASSI-L. These cut-points were applied to a new sample of older adults who were cognitive healthy controls (HC: n  = 26) and those on the Alzheimer’s disease (AD) continuum from early stage mild cognitive impairment (E-MCI: n  = 28), late stage MCI (L-MCI: n-18) to mild AD (AD: n  = 27). …Methods: All participants were administered the LASSI-L. All cognitively impaired participants were PET amyloid positive which likely reflects underlying AD neuropathology, while cognitively normal counterparts were deemed to have amyloid negative scans. Results: There was a monotonic relationship between the number of deficits on LASSI-L subscales and independent classification of study groups with greater severity of cognitive impairment. Importantly, taken together, impairment on maximum learning ability and measures of proactive semantic interference (both reflected by cued recall and intrusion errors) correctly classified 74.1% of EMCI, 94.4% of LMCI, and 96.3% of AD. Only 7.7% of HC were incorrectly classified as having impairments. Conclusion: A modest number of LASSI-L subscales taking approximately 8 minutes to administer, had excellent discriminative ability using established cut-offs among individuals with presumptive stages of AD. This has potential implications for both clinical practice and clinical research settings targeting AD during early prodromal stages. Show more

Keywords: Amyloid, biomarkers, cognitive screening, intrusion errors, mild cognitive impairment, neuroimaging, preclinical Alzheimer’s disease, semantic interference, structural MRI

DOI: 10.3233/JAD-200790

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

Authors: Menne, Felix | Schipke, Carola Gertrud | Klostermann, Arne | Fuentes-Casañ, Manuel | Freiesleben, Silka Dawn | Bauer, Chris | Peters, Oliver

Article Type: Research Article

Abstract: Background: Depressive symptoms often co-occur with Alzheimer’s disease (AD) and can impact neuropsychological test results. In early stages of AD, disentangling cognitive impairments due to depression from those due to neurodegeneration often poses a challenge. Objective: We aimed to identify neuropsychological tests able to detect AD-typical pathology while taking into account varying degrees of depressive symptoms. Methods: A battery of neuropsychological tests (CERAD-NP) and the Geriatric Depression Scale (GDS) were assessed, and cerebrospinal fluid (CSF) biomarkers were obtained. After stratifying patients into CSF positive or negative and into low, moderate, or high GDS score groups, sensitivity …and specificity and area under the curve (AUC) were calculated for each subtest. Results: 497 participants were included in the analyses. In patients with low GDS scores (≤10), the highest AUC (0.72) was achieved by Mini-Mental State Examination, followed by Constructional Praxis Recall and Wordlist Total Recall (AUC = 0.714, both). In patients with moderate (11–20) and high (≥21) GDS scores, Trail Making Test-B (TMT-B) revealed the highest AUCs with 0.77 and 0.82, respectively. Conclusion: Neuropsychological tests showing AD-typical pathology in participants with low GDS scores are in-line with previous results. In patients with higher GDS scores, TMT-B showed the best discrimination. This indicates the need to focus on executive function rather than on memory task results in depressed patients to explore a risk for AD. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, depression, executive function, memory, neuropsychology

DOI: 10.3233/JAD-200710

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

Authors: Gibson, Gary E. | Luchsinger, José A. | Cirio, Rosanna | Chen, Huanlian | Franchino-Elder, Jessica | Hirsch, Joseph A. | Bettendorff, Lucien | Chen, Zhengming | Flowers, Sarah | Gerber, Linda | Grandville, Thomas | Schupf, Nicole | Xu, Hui | Stern, Yaakov | Habeck, Christian | Jordan, Barry | Fonzetti, Pasquale

Article Type: Research Article

Abstract: Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s …Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p  = 0.125). Worsening in CDR was 77% lower (p  = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ 4 non-carriers. Benfotiamine significantly reduced increases in AGE (p  = 0.044), and this effect was stronger in the APOE ɛ 4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p  = 0.002). Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD. Show more

Keywords: Advanced glycation endproducts, Alzheimer’s disease, benfotiamine, glucose, inflammation, oxidative stress

DOI: 10.3233/JAD-200896

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2020

Authors: Werner, Perla | AboJabel, Hanan

Article Type: Research Article

Abstract: Background Engagement in behaviors aimed at reducing the risk of developing dementia is a leading recommendation in most National Dementia Strategy programs. Objective: In an effort to advance knowledge regarding the implementation of this recommendation, the current study examined the perceptions and engagement of the adult population in Israel regarding behaviors aimed at reducing the risk of developing dementia, and its correlates. Methods: A cross-sectional survey was conducted among 502 Israeli adults aged 40 and over. Approximately half of the participants (51.2% ) were female, and the majority (80.1% ) were Jewish. Results: Overall, …while the percentage of participants reporting that the examined activities were important for brain health was moderate, percentages reporting engaging in these behaviors were low. The most important correlate of engagement in health behaviors was participants’ perceptions about the importance of these behaviors for their brain health. Increased age, being Jewish, and enhanced perceived susceptibility to develop dementia were also significantly associated with increased engagement in behaviors to reduce the risk of dementia. Conclusion: The results of this study emphasize the need to develop intervention programs aimed at promoting engagement in behaviors to reduce the risk of dementia development. These programs will benefit from assessing participants’ perceived importance of these behaviors, and from identifying the needs of unique groups, such as older persons and those pertaining to ethno-cultural groups. Show more

Keywords: Behavior, brain health, dementia, perceptions, prevention, risk-reduction

DOI: 10.3233/JAD-200780

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

Authors: Kritikos, Minos | Gandy, Samuel | Meliker, Jaymie R. | Luft, Benjamin J. | Clouston, Sean A.P.

Article Type: Review Article

Abstract: An estimated 92% of the world’s population live in regions where people are regularly exposed to high levels of anthropogenic air pollution. Historically, research on the effects of air pollution have focused extensively on cardiovascular and pulmonary health. However, emerging evidence from animal and human studies has suggested that chronic exposures to air pollution detrimentally change the functioning of the central nervous system with the result being proteinopathy, neurocognitive impairment, and neurodegenerative disease. Case analyses of aging World Trade Center responders suggests that a single severe exposure may also induce a neuropathologic response. The goal of this report was to …explore the neuroscientific support for the hypothesis that inhaled particulate matter might cause an Alzheimer’s-like neurodegenerative disease, in order to consider proposed mechanisms and latency periods linking inhaled particulate matter and neurodegeneration, and to propose new directions in this line of research. Show more

Keywords: Cognitive impairment, dementia, exposures, inhalations, neurodegeneration, neuroinflammation, particulate matter, pathways, World Trade Center

DOI: 10.3233/JAD-200679

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Reschke-Hernández, Alaine E. | Belfi, Amy M. | Guzmán-Vélez, Edmarie | Tranel, Daniel

Article Type: Research Article

Abstract: Background: Research has indicated that individuals with Alzheimer’s-type dementia (AD) can experience prolonged emotions, even when they cannot recall the eliciting event. Less is known about whether music can modify the emotional state of individuals with AD and whether emotions evoked by music linger in the absence of a declarative memory for the eliciting event. Objective: We examined the effects of participant-selected recorded music on self-reported feelings of emotion in individuals with AD, and whether these feelings persisted irrespective of declarative memory for the emotion-inducing stimuli. Methods: Twenty participants with AD and 19 healthy comparisons (HCs) …listened to two 4.5-minute blocks of self-selected music that aimed to induce either sadness or happiness. Participants reported their feelings at baseline and three times post-induction and completed recall and recognition tests for the music selections after each induction. Results: Participants with AD had impaired memory for music selections compared to HCs. Both groups reported elevated sadness and negative affect after listening to sad music and increased happiness and positive affect after listening to happy music, relative to baseline. Sad/negative and happy/positive emotions endured up to 20 minutes post-induction. Conclusion: Brief exposure to music can induce strong and lingering emotions in individuals with AD. These findings extend the intriguing phenomenon whereby lasting emotions can be prompted by stimuli that are not remembered declaratively. Our results underscore the utility of familiar music for inducing emotions in individuals with AD and may ultimately inform strategies for using music listening as a therapeutic tool with this population. Show more

Keywords: Alzheimer’s disease, dementia, feelings, emotion, memory, music

DOI: 10.3233/JAD-200889

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

Authors: Marizzoni, Moira | Cattaneo, Annamaria | Mirabelli, Peppino | Festari, Cristina | Lopizzo, Nicola | Nicolosi, Valentina | Mombelli, Elisa | Mazzelli, Monica | Luongo, Delia | Naviglio, Daniele | Coppola, Luigi | Salvatore, Marco | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: Background: Metagenomic data support an association between certain bacterial strains and Alzheimer’s disease (AD), but their functional dynamics remain elusive. Objective: To investigate the association between amyloid pathology, bacterial products such as lipopolysaccharide (LPS) and short chain fatty acids (SCFAs: acetate, valerate, butyrate), inflammatory mediators, and markers of endothelial dysfunction in AD. Methods: Eighty-nine older persons with cognitive performance from normal to dementia underwent florbetapir amyloid PET and blood collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum. Blood levels of LPS was measured by ELISA, SCFAs by mass spectrometry, cytokines by using …real-time PCR, and biomarkers of endothelial dysfunction by flow cytometry. We investigated the association between the variables listed above with Spearman’s rank test. Results: Amyloid SUVR uptake was positively associated with blood LPS (rho≥0.32, p ≤0.006), acetate and valerate (rho≥0.45, p  < 0.001), pro-inflammatory cytokines (rho≥0.25, p ≤0.012), and biomarkers of endothelial dysfunction (rho≥0.25, p ≤0.042). In contrast, it was negatively correlated with butyrate (rho≤–0.42, p ≤0.020) and the anti-inflammatory cytokine IL10 (rho≤–0.26, p ≤0.009). Endothelial dysfunction was positively associated with pro-inflammatory cytokines, acetate and valerate (rho≥0.25, p ≤0.045) and negatively with butyrate and IL10 levels (rho≤–0.25, p ≤0.038). Conclusion: We report a novel association between gut microbiota-related products and systemic inflammation with brain amyloidosis via endothelial dysfunction, suggesting that SCFAs and LPS represent candidate pathophysiologic links between the gut microbiota and AD pathology. Show more

Keywords: Brain amyloidosis, inflammation, lipopolysaccharide, microbiota, short chain fatty acids

DOI: 10.3233/JAD-200306

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Matias-Guiu, Jordi A. | Pytel, Vanesa | Matías-Guiu, Jorge

Article Type: Short Communication

Abstract: We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a …higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD. Show more

Keywords: Alzheimer’s disease, care homes, COVID-19, frontotemporal dementia, SARS-CoV-2

DOI: 10.3233/JAD-200940

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Duggan, Michael R. | Torkzaban, Bahareh | Ahooyi, Taha Mohseni | Khalili, Kamel

Article Type: Review Article

Abstract: Across the fields of virology and neuroscience, the role of neurotropic viruses in Alzheimer’s disease (AD) has received renewed enthusiasm, with a particular focus on human herpesviruses (HHVs). Recent genomic analyses of brain tissue collections and investigations of the antimicrobial responses of amyloid-β do exclude a role of HHVs in contributing to or accelerating AD pathogenesis. Due to continued expansion in our aging cohort and the lack of effective treatments for AD, this composition examines a potential neuroviral theory of AD in light of these recent data. Consideration reveals a possible viral “Hit-and-Run” scenario of AD, as well as neurobiological …mechanisms (i.e., neuroinflammation, protein quality control, oxidative stress) that may increase risk for AD following neurotropic infection. Although limitations exist, this theoretical framework reveals several novel therapeutic targets that may prove efficacious in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, autophagy, herpesviruses, neuroinflammation

DOI: 10.3233/JAD-200814

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Jouvent, Eric | Alilli, Nassira | Hervé, Dominique | Chabriat, Hugues

Article Type: Short Communication

Abstract: In a woman with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) followed for 15 years, we observed magnetic resonance imaging white matter hyperintensities that vanished in the anterior temporal poles while the brain volume decreased unexpectedly. These imaging changes were transient and detected when the patient was being treated by valproic acid for stabilizing mood disturbances. This intriguing case supports that mechanisms underlying white matter hyperintensities can vary from one brain area to another and that important modifications of water influx into the brain tissue might be involved in some imaging features of CADASIL.

Keywords: Brain volume, CADASIL, valpromide, white matter hyperintensities

DOI: 10.3233/JAD-201086

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2020

Authors: Itzhaki, Ruth F.

Article Type: Article Commentary

Abstract: A recent study in vitro has shown that a sulphated polysaccharide, a type of fucoidan, has potent antiviral activity against SARS-Cov2. If the antiviral action were successful also for COVID-19 patients, it would be enormously valuable against not only acute disease but also long-term mental effects, which might include Alzheimer’s disease (AD). In a trial of AD patients, the apparent success of treatment with a polysaccharide, GV971, was suggested to result from antiviral action against herpes simplex virus type 1 (HSV1) in brain, a pathogen strongly implicated in AD, and that sulphation of GV971, making it fucoidan-like, might increase …its putative antiviral action. These data indicate that treatment of AD patients might be very effective using valacyclovir, a conventional antiviral, which inhibits viral replication, together with a fucoidan, which blocks virus entry into cells. Show more

Keywords: Alzheimer’s disease, antiviral, COVID-19, fucoidans, Herpes simplex virus type 1, SARS-Cov2

DOI: 10.3233/JAD-200986

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2020

Authors: Haapanen, Marjut | Katisko, Kasper | Hänninen, Tuomo | Krüger, Johanna | Hartikainen, Päivi | Haapasalo, Annakaisa | Remes, Anne M. | Solje, Eino

Article Type: Research Article

Abstract: Primary progressive aphasia (PPA) forms the spectrum of language variants of frontotemporal lobar degeneration (FTLD), including three subtypes each consisting of distinctive speech and language features. Repeat expansion in C9orf72 gene is the most common genetic cause of FTLD. However, thus far only little is known about the effects of the C9orf72 repeat expansion on the phenotype of PPA. This retrospective study aimed at determining the differences between the PPA phenotypes of the C9orf72 expansion carriers and non-carriers. Our results demonstrated no significant differences between these groups, indicating that the C9orf72 repeat expansion does not substantially …affect the phenotype of PPA. Show more

Keywords: C9orf72, frontotemporal dementia, frontotemporal lobar degeneration, primary progressive aphasia

DOI: 10.3233/JAD-200795

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

Authors: Khalsa, Dharma Singh

Article Type: Book Review

DOI: 10.3233/JAD-201157

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2020

Authors: Martín-Jiménez, Paloma | Muñoz-García, Mariana I. | Seoane, David | Roca-Rodríguez, Lucas | García-Reyne, Ana | Lalueza, Antonio | Maestro, Guillermo | Folgueira, Dolores | Blanco-Palmero, Víctor A. | Herrero-San Martín, Alejandro | Llamas-Velasco, Sara | Pérez-Martínez, David A. | González-Sánchez, Marta | Villarejo-Galende, Alberto

Article Type: Short Communication

Abstract: We analyzed the frequency of cognitive impairment (CI) in deceased COVID-19 patients at a tertiary hospital in Spain. Among the 477 adult cases who died after admission from March 1 to March 31, 2020, 281 had confirmed COVID-19. CI (21.1% dementia and 8.9% mild cognitive impairment) was a common comorbidity. Subjects with CI were older, tended to live in nursing homes, had shorter time from symptom onset to death, and were rarely admitted to the ICU, receiving palliative care more often. CI is a frequent comorbidity in deceased COVID-19 subjects and is associated with differences in care.

Keywords: Cognitive impairment, COVID-19, dementia, morbidity, mortality

DOI: 10.3233/JAD-200937

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Zhang, Tianying | Han, Xiaojuan | Zhang, Xiaohua | Chen, Zhi | Mi, Yajing | Gou, Xingchun

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by brain function disorder and chronic cognitive function impairment. The onset of AD is complex and is mostly attributed to interactions between genetic factors and environmental factors. Lifestyle, dietary habits, and food consumption are likely to play indispensable functions in aged-related neurodegenerative diseases in elderly people. An increasing number of epidemiological studies have linked dietary fatty acid factors to AD, raising the point of view that fatty acid metabolism plays an important role in AD initiation and progression as well as in other central nervous system disorders. In this paper, we …review the effects of the consumption of various dietary fatty acids on AD onset and progression and discuss the detrimental and beneficial effects of some typical fatty acids derived from dietary patterns on the pathology of AD. We outline these recent advances, and we recommend that healthy dietary lifestyles may contribute to preventing the occurrence and decreasing the pathology of AD. Show more

Keywords: Alzheimer’s disease, fatty acid, ketone body, MUFA, PUFA

DOI: 10.3233/JAD-200558

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Krell-Roesch, Janina | Syrjanen, Jeremy A. | Mielke, Michelle M. | Christianson, Teresa J. | Kremers, Walter K. | Machulda, Mary M. | Knopman, David S. | Petersen, Ronald C. | Vassilaki, Maria | Geda, Yonas E.

Article Type: Short Communication

Abstract: We examined the associations between baseline neuropsychiatric symptoms (NPS) and longitudinal changes in functional performance among 5,394 non-demented individuals aged ≥50 years (2,729 males; median age 74.2 years; 4,716 cognitively unimpaired, 678 mild cognitive impairment). After adjusting for age, sex, education, and medical comorbidities, NPS assessed by the Neuropsychiatric Inventory Questionnaire, clinical depression (Beck Depression Inventory score ≥13) and anxiety (Beck Anxiety Inventory score ≥10) were significantly associated with an increase in the Functional Activities Questionnaire score, indicating functional decline over time. This association may vary depending on the degree of cognitive impairment at baseline.

Keywords: Anxiety, depression, functional performance

DOI: 10.3233/JAD-200764

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

Authors: Loupy, Kelsey M. | Lee, Thomas | Zambrano, Cristian A. | Elsayed, Ahmed I. | D’Angelo, Heather M. | Fonken, Laura K. | Frank, Matthew G. | Maier, Steven F. | Lowry, Christopher A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is an inflammatory neurodegenerative disease that may be associated with prior bacterial infections. Microbial “old friends” can suppress exaggerated inflammation in response to disease-causing infections or increase clearance of pathogens such as Mycobacterium tuberculosis , which causes tuberculosis (TB). One such “old friend” is Mycobacterium vaccae NCTC 11659, a soil-derived bacterium that has been proposed either as a vaccine for prevention of TB, or as immunotherapy for the treatment of TB when used alongside first line anti-TB drug treatment. Objective: The goal of this study was to use a hypothesis generating approach to …explore the effects of M. vaccae on physiological changes in the plasma and cerebrospinal fluid (CSF). Methods: Liquid chromatography-tandem mass spectrometry-based proteomics were performed in plasma and CSF of adult male rats after immunization with a heat-killed preparation of M. vaccae NCTC 11659 or borate-buffered saline vehicle. Gene enrichment analysis and protein-protein interactions were performed to integrate physiological network changes in plasma and CSF. We used RT-qPCR to assess immune and metabolic gene expression changes in the hippocampus. Results: In both plasma and CSF, immunization with M. vaccae increased proteins associated with immune activation and downregulated proteins corresponding to lipid (including phospholipid and cholesterol) metabolism. Immunization with M. vaccae also increased hippocampal expression of interleukin-4 (IL-4) mRNA, implicating anti-inflammatory effects in the central nervous system. Conclusion: M. vaccae alters host immune activity and lipid metabolism. These data are consistent with the hypothesis that microbe-host interactions may protect against possible infection-induced, inflammation-related cognitive impairments. Show more

Keywords: Alzheimer’s disease, ApoA-I, ApoC-II, cerebrospinal fluid, inflammation, lipid metabolism, mycobacteria, neurodegenerative disorder, neuroimmunomodulation, proteomics

DOI: 10.3233/JAD-200568

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

Authors: Ruiter, Marvin | Herstel, Lotte J. | Wierenga, Corette J.

Article Type: Research Article

Abstract: Background: In an early stage of Alzheimer’s disease (AD), before the formation of amyloid plaques, neuronal network hyperactivity has been reported in both patients and animal models. This suggests an underlying disturbance of the balance between excitation and inhibition. Several studies have highlighted the role of somatic inhibition in early AD, while less is known about dendritic inhibition. Objective: In this study we investigated how inhibitory synaptic currents are affected by elevated Aβ levels. Methods: We performed whole-cell patch clamp recordings of CA1 pyramidal neurons in organotypic hippocampal slice cultures after treatment with Aβ-oligomers and in …hippocampal brain slices from AppNl - F - G mice (APP-KI). Results: We found a reduction of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in organotypic slices after 24 h Aβ treatment. sIPSCs with slow rise times were reduced, suggesting a specific loss of dendritic inhibitory inputs. As miniature IPSCs and synaptic density were unaffected, these results suggest a decrease in activity-dependent release after Aβ treatment. We observed a similar, although weaker reduction in sIPSCs in CA1 pyramidal neurons from APP-KI mice compared to control. When separated by sex, the strongest reduction in sIPSC frequency was found in slices from male APP-KI mice. Consistent with hyperexcitability in pyramidal cells, dendritically targeting interneurons received slightly more excitatory input. GABAergic action potentials had faster kinetics in APP-KI slices. Conclusion: Our results show that Aβ affects dendritic inhibition via impaired action potential driven release, possibly due to altered kinetics of GABAergic action potentials. Reduced dendritic inhibition may contribute to neuronal hyperactivity in early AD. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, neural inhibition, synaptic transmission

DOI: 10.3233/JAD-200527

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

Authors: Gabere, Musa | Thu Pham, Nha Trang | Graff-Radford, Jonathan | Machulda, Mary M. | Duffy, Joseph R. | Josephs, Keith A. | Whitwell, Jennifer L. | for Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer’s disease (AD). Both PCA and LPA are associated with relative sparing of hippocampus compared to neocortex, although hippocampal atrophy is observed. It is unclear whether regional patterns of hippocampal subfield involvement differ between PCA and LPA, and whether they differ from typical AD. Objective: To assess volume of specific subfields of the hippocampus in PCA, LPA, and typical AD. Methods: Fifty-nine patients with PCA and 77 patients with LPA were recruited and underwent T1-weighted MRI and …Pittsburgh Compound B (PiB) PET at Mayo Clinic. Thirty-six probable AD patients and 100 controls were identified from the Alzheimer’s Disease Neuroimaging Initiative. Hippocampal subfield volumes were calculated using Freesurfer, and volumes were compared between PCA, LPA, AD, and controls using Kruskal-Wallis and Dunn tests. Results: The LPA and PCA groups both showed the most striking abnormalities in CA4, presubiculum, molecular layer of the hippocampus, molecular and granule cell layers of the dentate gyrus, and the hippocampal-amygdala transition area, although atrophy was left-sided in LPA. PCA showed smaller volume of right presubiculum compared to LPA, with trends for smaller volumes of right parasubiculum and fimbria. LPA showed a trend for smaller volumes of left CA1 compared to PCA. The AD group showed smaller volumes of the right subiculum, CA1, and presubiculum compared to LPA. Conclusion: Patterns of hippocampal subfield atrophy differ across the different syndromic variants of AD. Show more

Keywords: Alzheimer’s disease, hippocampal subfields, hippocampus, logopenic progressive aphasia, magnetic resonance imaging, posterior cortical atrophy

DOI: 10.3233/JAD-200625

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

Authors: Oviedo, Diana C. | Perez-Lao, Ambar R. | Flores-Cuadra, Julio A. | Villarreal, Alcibiades E. | Carreira, Maria B. | Grajales, Shantal A. | Britton, Gabrielle B.

Article Type: Short Communication

Abstract: Apolipoprotein ɛ 4 allele (APOE ɛ 4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), but inconsistencies have arisen in studies with Hispanics. The objective of this study was to explore APOE ɛ 4 expression and cognitive function in a sample of Panamanian older adults, including healthy controls, mild cognitive impairment, and AD. Participants with at least one copy of APOE ɛ 4 had a significantly lower performance in global cognition, verbal memory, executive functions, visuospatial abilities, regardless of diagnosis. The present study contributes to the understanding of the association of APOE ɛ …4 and impairment in specific cognitive domains in elderly Hispanics. Show more

Keywords: Alzheimer’s disease, biomarkers, cognition, memory deficits

DOI: 10.3233/JAD-200921

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

Authors: Rosin, Eric R. | Blasco, Drew | Pilozzi, Alexander R. | Yang, Lawrence H. | Huang, Xudong

Article Type: Review Article

Abstract: As the most common form of senile dementia, Alzheimer’s disease (AD) is accompanied by a great deal of uncertainty which can lead to fear and stigma for those identified with this devastating disease. As the AD definition evolves from a syndromal to a biological construct, and early diagnoses becomes more commonplace, more confusion and stigma may result. We conducted a narrative review of the literature on AD stigma to consolidate information on this body of research. From the perspective of several stigma theories, we identified relevant studies to inform our understanding of the way in which implementation of the new …framework for a biological based AD diagnosis may have resulted in new and emerging stigma. Herein, we discuss the emergence of new AD stigma as our understanding of the definition of the disease changes. We further propose recommendations for future research to reduce the stigma associated with AD. Show more

Keywords: Aging, Alzheimer’s disease, dementia, mild cognitive impairment, stigma, subjective cognitive impairment

DOI: 10.3233/JAD-200932

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

Authors: Hu, Emily A. | Wu, Aozhou | Dearborn, Jennifer L. | Gottesman, Rebecca F. | Richey Sharrett, A. | Steffen, Lyn M. | Coresh, Josef | Rebholz, Casey M.

Article Type: Research Article

Abstract: Background: Previous studies have suggested that adherence to healthy dietary patterns during late life may be associated with improved cognition. However, few studies have examined the association between healthy dietary patterns during midlife and incident dementia. Objective: Our study aimed to determine the association between adherence to healthy dietary patterns at midlife and incident dementia. Methods: We included 13,630 adults from the Atherosclerosis Risk in Communities (ARIC) Study in our prospective analysis. We used food frequency questionnaire responses to calculate four dietary scores: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean (aMed) diet, …and Dietary Approaches to Stop Hypertension (DASH). Participants were followed until the end of 2017 for incident dementia. Cox regression models adjusted for covariates were used to estimate risk of incident dementia by quintile of dietary scores. Results: Over a median of 27 years, there were 2,352 cases of incident dementia documented. Compared with participants in quintile 1 of HEI-2015, participants in quintile 5 (healthiest) had a 14% lower risk of incident dementia (hazard ratio, HR: 0.86, 95% confidence interval, CI: 0.74–0.99). There were no significant associations of incident dementia with the AHEI-2010, aMed, or DASH scores. There were no significant interactions by sex, age, race, education, physical activity, hypertension, or obesity. Conclusion: Adherence to the HEI-2015, but not the other dietary scores, during midlife was associated with lower risk of incident dementia. Further research is needed to elucidate whether timing of a healthy diet may influence dementia risk. Show more

Keywords: AHEI-2010, cognition, DASH, dementia, dietary pattern, HEI-2015, Mediterranean diet

DOI: 10.3233/JAD-200392

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Hüttenrauch, Melanie | Lopez-Noguerola, José Sócrates | Castro-Obregón, Susana

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a complex, multifactorial neurodegenerative disorder that represents a major and increasing global health challenge. In most cases, the first clinical symptoms of AD are preceded by neuropathological changes in the brain that develop years to decades before their onset. Therefore, research in the last years has focused on this preclinical stage of AD trying to discover intervention strategies that might, if implemented effectively, delay or prevent disease progression. Among those strategies, mind-body therapies such as yoga and meditation have gained increasing interest as complementary alternative interventions. Several studies have reported a positive impact of yoga and …meditation on brain health in both healthy older adults and dementia patients. However, the underlying neurobiological mechanisms contributing to these effects are currently not known in detail. More specifically, it is not known whether yogic interventions, directly or indirectly, can modulate risk factors or pathological mechanisms involved in the development of dementia. In this article, we first review the literature on the effects of yogic practices on outcomes such as cognitive functioning and neuropsychiatric symptoms in patients with mild cognitive impairment and dementia. Then, we analyze how yogic interventions affect different risk factors as well as aspects of AD pathophysiology based on observations of studies in healthy individuals or subjects with other conditions than dementia. Finally, we integrate this evidence and propose possible mechanisms that might explain the positive effects of yogic interventions in cognitively impaired individuals. Show more

Keywords: Alzheimer’s disease, dementia, mind-body therapy, mild cognitive impairment, meditation, yoga

DOI: 10.3233/JAD-200743

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2020

Authors: Huang, Zhenting | Yan, Qian | Wang, Yangyang | Zou, Qian | Li, Jing | Liu, Zhou | Cai, Zhiyou

Article Type: Review Article

Abstract: Mitochondrial dysfunction has been widely reported in several neurodegenerative disorders, including in the brains of patients with Alzheimer’s disease (AD), Parkinson’s disease, and Huntington disease. An increasing number of studies have implicated altered glucose and energy metabolism in patients with AD. There is compelling evidence of abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase and α -ketoglutarate dehydrogenase complexes, which play a great significance role in the pathogenesis of AD. Changes in some of the enzyme activities of the mitochondria found in AD have been linked with the pathology of amyloid-β (Aβ). …This review highlights the role of mitochondrial function in the production and clearance of Aβ and how the pathology of Aβ leads to a decrease in energy metabolism by affecting mitochondrial function. Show more

Keywords: Alzheimer’s disease, amyloid-β , dysfunction, mitochondria, pathology

DOI: 10.3233/JAD-200519

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

Authors: Khedr, Eman M. | Gomaa, Asmaa M.S. | Ahmed, Omyma G. | Sayed, Hanaa M.M. | Gamea, Ayman

Article Type: Research Article

Abstract: Background: There are currently few biomarkers to assist in early diagnosis of dementias. Objective: To distinguish between different dementias: Alzheimer’s disease (AD), vascular dementia (VaD), and Parkinson’s disease dementia (PDD) using simple neurophysiologic (P300) and laboratory markers (transforming growth factor β 1 “TGF-β 1”). Methods: The study included 15 patients for each type of dementia and 25 age- and sex-matched control subjects. Dementia patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition-revised (DSM-IV-R). Modified Mini-Mental State Examination (3MS), Memory Assessment Scale (MAS), P300, and TGF-β 1 were examined for each …participant. Results: There were no significant differences between groups as regard to age, sex, and education, social, and economic levels. Significant differences between groups were observed in registration and naming variables of the 3MS. Compared with the control group, P300 latency was prolonged in all groups, although to a greater extent in AD and PDD than in VaD. A serum level of TGF-β 1 was significantly elevated in all groups but was significantly higher in AD and VaD than in PDD. 3MS tended to correlate with P300 more than TGF-β 1, and to be stronger in AD than the other groups. Conclusion: Measurements of P300 latency and serum levels of TGF-β 1 can help distinguish AD, PDD, and VaD. P300 was more prolonged in AD and PDD than VaD whereas TGF-β 1 was significantly higher in AD and VaD than PDD. Thus P300 and TGF-β 1 may be useful biomarkers for detection and evaluation of the extent of cognitive dysfunction. Show more

Keywords: Alzheimer’s disease, event related potential P300, Modified Mini-Mental State Examination, Parkinson’s disease dementia, transforming growth factor β1, vascular dementia

DOI: 10.3233/JAD-200885

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Tsolaki, Magda | Lazarou, Eftychia | Kozori, Mahi | Petridou, Niki | Tabakis, Irene | Lazarou, Ioulietta | Karakota, Maria | Saoulidis, Iordanis | Melliou, Eleni | Magiatis, Prokopios

Article Type: Research Article

Abstract: Background: Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function. Objective: To investigate for the first time the effect of Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) in people with mild cognitive impairment (MCI). Methods: We conducted a randomized prospective study so as to examine the HP-EH-EVOO and MP-EVOO versus MeDi in MCI. Genetic predisposition (APOE ɛ 4) to Alzheimer’s disease (AD) was tested and an extensive neuropsychological battery was administered at baseline and after 12 months. Each …participant was randomized and assigned one of three groups: 1) Group 1 received the HP-EH-EVOO (50 mL/day); 2) Group 2 received the MP-EVOO (50 mL/day), and 3) Group 3 received only the MeDi instructions. Results: Better follow-up performance was found in Group 1 compared to Group 2 and Group 3 in the almost all cognitive domains. Moreover, Group 2 showed also significant improvement compared to Group 3 in ADAS-cog (p  = 0.001) and MMSE (p  = 0.05), whereas Group 3 exhibited worse or similar to baseline performance in almost all domains. In particular, Group 1 and Group 2 had better outcomes with regards to ADAS-cog (p  = 0.003), Digit Span (p  = 0.006), and Letter fluency (p  = 0.003). Moreover, there was a significant difference (p  = 0.001) in the presence of APOE ɛ 4 between the Groups 1 and 2 versus Group 3. Conclusion: Long-term intervention with HP-EH-EVOO or MP-EVOO was associated with significant improvement in cognitive function compared to MeDi, independent of the presence of APOE ɛ 4. Show more

Keywords: Alzheimer’s disease, APOE, extra virgin olive oil, Mediterranean Diet, mild cognitive impairment, natural compounds, non-pharmaceutical interventions

DOI: 10.3233/JAD-200405

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

Authors: Snowden, Taylor M. | Hinde, Anthony K. | Reid, Hannah M.O. | Christie, Brian R.

Article Type: Research Article

Abstract: Background: Mild traumatic brain injury (mTBI) is a putative risk factor for dementia; however, despite having apparent face validity, the evidence supporting this hypothesis remains inconclusive. Understanding the role of mTBI as a risk factor is becoming increasingly important given the high prevalence of mTBI, and the increasing societal burden of dementia. Objective: Our objective was to use the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) format to determine if an association exists between mTBI and dementia and related factors, and to quantify the degree of risk. Methods: In this format, two authors conducted …independent database searches of PubMed, PsycInfo, and CINAHL using three search blocks to find relevant papers published between 2000 and 2020. Relevant studies were selected using pre-defined inclusion/exclusion criteria, and bias scoring was performed independently by the two authors before a subset of studies was selected for meta-analysis. Twenty-one studies met the inclusion criteria for this systematic review. Results: The meta-analysis yielded a pooled odds ratio of 1.96 (95% CI 1.698–2.263), meaning individuals were 1.96 times more likely to be diagnosed with dementia if they had a prior mTBI. Most studies examining neuropsychiatric and neuroimaging correlates of dementia found subtle, persistent changes after mTBI. Conclusion: These results indicate that mTBI is a risk factor for the development of dementia and causes subtle changes in performance on neuropsychiatric testing and brain structure in some patients. Show more

Keywords: Alzheimer’s disease, dementia, mild traumatic brain injury

DOI: 10.3233/JAD-200662

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Stonnington, Cynthia M. | Velgos, Stefanie N. | Chen, Yinghua | Syed, Sameena | Huentelman, Matt | Thiyyagura, Pradeep | Lee, Wendy | Richholt, Ryan | Caselli, Richard J. | Locke, Dona E.C. | Lu, Bai | Reiman, Eric M. | Su, Yi | Chen, Kewei

Article Type: Research Article

Abstract: Background: Whether brain-derived neurotrophic factor (BDNF ) Met carriage impacts the risk or progression of Alzheimer’s disease (AD) is unknown. Objective: To evaluate the interaction of BDNF Met and APOE 4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study. Methods: 114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B …(PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years. Results: Among APOE 4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE 4 non-carriers. Conclusion: Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE 4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity—findings that would need to be confirmed in larger studies. Show more

Keywords: Amyloid, APOE4, BDNF, cognition, fluorodeoxyglucose F18, positron emission tomography

DOI: 10.3233/JAD-200132

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

Authors: El Haj, Mohamad | Allain, Philippe | Annweiler, Cédric | Boutoleau-Bretonnière, Claire | Chapelet, Guillaume | Gallouj, Karim | Kapogiannis, Dimitrios | Roche, Jean | Boudoukha, Abdel Halim

Article Type: Research Article

Abstract: Background/Objective: The COVID-19 crisis has been increasing the burden of healthcare workers in acute care geriatric facilities. These workers have been dealing with drastic changes in the care they provide to their residents including cancelation of group activities and communal dining and even restrictions of activities outside rooms. Healthcare workers have also been devoting more time and energy to perform COVID-related medical duties. Geriatric facilities have been facing shortages in equipment and supplies, as well as staffing shortages. Finally, healthcare workers have been facing challenges regarding their personal safety and that of their families. Consequently, we hypothesized the presence of …high levels of burnout among healthcare workers during the COVID-19 crisis. Methods: To evaluate burnout in healthcare workers in French acute care geriatric facilities, we used an online survey based on the Oldenburg Burnout Inventory. Eighty-four healthcare workers answered the survey, during April of 2020. Results: Analysis demonstrated that they were experiencing medium levels of burnout, exhaustion, and disengagement. Conclusion: This level of burnout reflected their fatigue, loss of energy, and/or feelings of being overextended and exhausted. Considering the expected cumulative impact of various stressors, the medium level of burnout observed has come as a surprise to us and might actually be considered as relatively good news. Nevertheless, no level of burnout is negligible and has wide ranging negative consequences. Show more

Keywords: Burnout, caregivers, COVID-19, geriatric facilities

DOI: 10.3233/JAD-201029

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Ravona-Springer, Ramit | Sharvit-Ginon, Inbal | Ganmore, Ithamar | Greenbaum, Lior | Bendlin, Barbara B. | Sternberg, Shelley A. | Livny, Abigail | Domachevsky, Liran | Sandler, Israel | Ben Haim, Simona | Golan, Sapir | Ben-Ami, Liat | Lesman- Segev, Orit | Manzali, Sigalit | Heymann, Anthony | Beeri, Michal Schnaider

Article Type: Research Article

Abstract: Background: Family history of Alzheimer’s disease (AD) is associated with increased dementia-risk. Objective: The Israel Registry for Alzheimer’s Prevention (IRAP) is a prospective longitudinal study of asymptomatic middle-aged offspring of AD patients (family history positive; FH+) and controls (whose parents have aged without dementia; FH–) aimed to unravel the contribution of midlife factors to future cognitive decline and dementia. Here we present the study design, methods, and baseline characteristics. Methods: Participants are members of the Maccabi Health Services, 40–65 years of age, with exquisitely detailed laboratory, medical diagnoses and medication data available in the Maccabi electronic …medical records since 1998. Data collected through IRAP include genetic, sociodemographic, cognitive, brain imaging, lifestyle, and health-related characteristics at baseline and every three years thereafter. Results: Currently IRAP has 483 participants [mean age 54.95 (SD = 6.68) and 64.8% (n  = 313) women], 379 (78.5%) FH+, and 104 (21.5%) FH–. Compared to FH–, FH+ participants were younger (p  = 0.011), more often males (p  = 0.003) and with a higher prevalence of the APOE E4 allele (32.8% FH+, 22% FH–; p  = 0.040). Adjusting for age, sex, and education, FH+ performed worse than FH–in global cognition (p  = 0.027) and episodic memory (p  = 0.022). Conclusion: Lower cognitive scores and higher rates of the APOE E4 allele among the FH+ group suggest that FH ascertainment is good. The combination of long-term historical health-related data available through Maccabi with the multifactorial information collected through IRAP will potentially enable development of dementia-prevention strategies already in midlife, a critical period in terms of risk factor exposure and initiation of AD-neuropathology. Show more

Keywords: Alzheimer’s disease, APOE E4, family history, offspring, risk factors

DOI: 10.3233/JAD-200623

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

Authors: Chang, Kuo-Hsuan | Huang, Ching-Chang | Chen, Chiung-Mei | Wu, Hsiu-Chuan | Kuo, Hung-Chou

Article Type: Research Article

Abstract: Background: The behavioral and psychological symptoms of dementia (BPSD) seriously affect the quality of life of patients with Alzheimer’s disease (AD) and their caregivers. Objective: We aimed to identify associations between demographic/genetic factors and clinical presentations of BPSD. Methods: In a cohort of 463 AD patients with BPSD, we retrospectively analyzed sex, education level, AD severity (assessed using the Clinical Dementia Rating and Mini-Mental Status Examination), and BPSD severity (assessed using the Neuropsychiatry Inventory, NPI). Severe BPSD was defined as NPI ≥10 for 3 consecutive years. Results: Among patients with severe BPSD (NPI ≥10), …we observed more female patients (62.96%) and a lower level of education (6.03±4.77 years) as compared to those with mild BPSD (NPI <10) (female: 51.09%, p  = 0.007; education years: 7.91±4.93, p  <  0.001). Females had a lower level of education (5.72±4.50 years) and higher scores for depression/dysphoria (1.22±2.05) compared with males (education: 8.96±4.89 years, p  <  0.001; depression/dysphoria: 0.78±1.42, p  = 0.047). Patients with a high level of education (defined as ≥12 years) had higher scores for appetite/eating (0.90±2.02) than did those without (0.69±1.79; p  = 0.001). Genetic analysis showed similar total and subscale NPI scores between patients with and without APOE4 and with and without the GRN rs5848 genotype. Conclusion: Our findings indicate potential contributions of sex and education to the presentation of BPSD. Further study is warranted to provide models for tailoring therapeutic programs to individual AD patients according to these factors. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, education level, Neuropsychiatric Inventory, sex

DOI: 10.3233/JAD-200507

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Gao, Ling | Wang, Jin | Jiang, Yu | Wei, Shan | Shang, Suhang | Chen, Chen | Dang, Liangjun | Huo, Kang | Deng, Meiying | Wang, Jingyi | Qu, Qiumin

Article Type: Research Article

Abstract: Background: Transport proteins, soluble LRP1 (sLRP1) and soluble RAGE (sRAGE), play a pivotal role in the peripheral clearance of plasma amyloid-β (Aβ). However, their relationship is seldom discussed, especially in Alzheimer’s disease (AD). Objective: To explore whether their relationship in patients with AD varied from those in cognitively normal (CN) controls. Methods: We initially recruited 70 patients with AD and 725 CN controls, then applied propensity score matching (PSM) analysis to balance the differences between two groups. Plasma levels of sLRP1, sRAGE, and Aβ were measured using commercial ELISA kits and log transformed when skewed distributed. …The relationship between sLRP1/sRAGE and plasma Aβ were analyzed using Pearson’s correlation analysis followed by multiple linear regression separately in the original population and matched participants. Results: After PSM, 70 patients with AD and 140 matched controls were included for further analysis. Log sLRP1 was positively correlated with plasma Aβ40 in matched CN controls (r  = 0.222, p  = 0.008) but not in patients with AD (r  = 0.137, p  = 0.260). After multivariable adjustment, Log sLRP1 remained significantly associated with plasma Aβ40 in the CN group (β= 7.347, p  = 0.014) but not in the AD group (β= 10.409, p  = 0.105). In contrast, Log sLRP1 was not correlated with plasma Aβ42 in patients with AD or CN controls, and Log sRAGE was consistently not associated with plasma Aβ40 or Aβ42 in either group. Conclusion: The significant correlation between sLRP1 and plasma Aβ40 present in CN controls was not found in patients with AD, suggesting that their relationship was different in AD. However, the specific mechanisms and its influence on cerebral amyloid burden require further validation. Show more

Keywords: Alzheimer’s disease, plasma amyloid-β, propensity score matching, soluble low-density lipoprotein receptor-related protein-1, soluble receptor of advanced glycation end products

DOI: 10.3233/JAD-191320

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

Authors: Gavriel, Yuval | Rabinovich-Nikitin, Inna | Ezra, Assaf | Barbiro, Becki | Solomon, Beka

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifest simultaneously, leading to cognitive impairment and death. Amyloid-β (Aβ) accumulation in the brain triggers the onset of AD, accompanied by neuroinflammatory response and pathological changes. The CXCR4/CXCL12 (SDF1) axis is one of the major signal transduction cascades involved in the inflammation process and regulation of homing of hematopoietic stem cells (HSCs) within the bone marrow niche. Inhibition of the axis with AMD3100, a reversible antagonist of CXCR4 mobilizes endogenous HSCs from the bone marrow into the periphery, facilitating the recruitment of bone …marrow-derived microglia-like cells into the brain, attenuates the neuroinflammation process that involves release of excitotoxic markers such as TNFα , intracellular Ca2 + , and glutamate and upregulates monocarboxylate transporter 1, the major L-lactate transporter in the brain. Objective: Herein, we investigate if administration of a combination of AMD3100 and L-lactate may have beneficial effects in the treatment of AD. Methods: We tested the feasibility of the combined treatment for short- and long-term efficacy for inducing endogenous stem cells’ mobilization and attenuation of neuroinflammation in two distinct amyloid-β-induced AD mouse models. Results: The combined treatment did not demonstrate any adverse effects on the mice, and resulted in a significant improvement in cognitive/memory functions, attenuated neuroinflammation, and alleviated AD pathologies compared to each treatment alone. Conclusion: This study showed AMD3100’s beneficial effect in ameliorating AD pathogenesis, suggesting an alternative to the multistep procedures of transplantation of stem cells in the treatment of AD. Show more

Keywords: Alzheimer’s disease, bone marrow-derived macrophages, CXCR4/SDF1 axis, inflammation, hematopoietic stem cells, L-lactate, MCT1, Plerixafor, tumor necrosis factor-alpha, tumor suppressor protein p53

DOI: 10.3233/JAD-200506

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Xu, Zhongzhi | Yang, Jiannan | Kai Lau, Kui | Yip, Paul S.F. | Wong, Ian C.K. | Zhang, Qingpeng

Article Type: Research Article

Abstract: Background: Given concerns about adverse outcomes for older people taking antidepressants in the literature, we investigated whether taking antidepressants elevates the risk of dementia. Objective: This study aims to investigate the putative association of antidepressants with the risk of dementia. Methods: We conducted a population-based self-controlled case series analysis of older people with dementia and taking antidepressants, using territory-wide medical records of 194,507 older patients collected by the Hospital Authority of Hong Kong, to investigate the association between antidepressant treatment and the risk of developing dementia in older people. Results: There was a significantly …higher risk of being diagnosed with dementia during the pre-drug-exposed period (incidence rate ratio (IRR) 20.42 (95% CI: 18.66–22.34)) compared to the non-drug-exposed baseline period. The IRR remained high during the drug-exposed period (IRR 8.86 (7.80–10.06)) before returning to a baseline level after washout (IRR 1.12 (0.77–1.36)). Conclusion: The higher risk of dementia before antidepressant treatment may be related to emerging psychiatric symptoms co-occurring with dementia, which trigger medical consultations that result in a decision to begin antidepressants. Our findings do not support a causal relationship between antidepressant treatment and the risk of dementia. Show more

Keywords: Alzheimer’s disease, antidepressants, causal associations, dementia, self-controlled case series studies

DOI: 10.3233/JAD-200875

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

Authors: Wang, Jianjun | Lyu, Hanqing | Chen, Jianxiang | Lin, Songjun | Zheng, Haotao | Li, Jinfang | Kong, Fanxin | Gao, Jinyun | Yu, Haibo | Hu, Yuanming | Guo, Zhouke

Article Type: Research Article

Abstract: Background: Late-life depression often coexists with vascular cognitive impairment and affects the quality of life for elders. However, little is known about cortical morphometric interactions between subcortical vascular mild cognitive impairment (svMCI) and concomitant mild depressive symptoms at the early stage. Objective: We aimed to investigate cortical alterations of svMCI with and without depressive symptoms and determine whether these parameters are associated with depression symptoms and/or cognitive impairments. Methods: Surface based morphometry was performed on 18 svMCI patients with depressive symptoms (svMCI + D), 16 svMCI patients without depressive symptoms (svMCI–D), and 23 normal controls (NC). …Results: Compared to NC, both svMCI + D and svMCI–D patients exhibited significantly decreased surface area (SA) in many cortical areas. Interestingly, svMCI + D patients showed significantly increased rather than decreased SA in right lateral occipital gyrus (LOG.R), and a consistent trend of increased SA in these areas compared to svMCI–D. In addition, the svMCI + D showed increased gray matter volume of left pericalcarine (periCAL.L) than svMCI_D, whereas svMCI_D showed decreased gray matter volume of periCAL.L than NC. Further correlation analyses revealed that the SA of left superior temporal gyrus (STG.L) and right lateral orbital part of frontal gyrus (lorbFG.R) were significantly correlated with Hamilton depression rating scale of svMCI + D. Conclusion: In conclusion, these results extend our insight into svMCI and add weight to reevaluation of concomitant early stage depressive symptoms. Moreover, we suggest that LOG.R∖periCAL.L∖STG.L∖lorbFG.R might serve as sensitive and trait-dependent biomarkers to detect concomitant depressive symptoms in svMCI patients. Show more

Keywords: Depression symptoms, gray matter volume, subcortical vascular mild cognitive impairment, surface-based morphometry, surface area

DOI: 10.3233/JAD-200156

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Lee, Jun Ho | Byun, Min Soo | Yi, Dahyun | Ko, Kang | Jeon, So Yeon | Sohn, Bo Kyung | Lee, Jun-Young | Lee, Younghwa | Joung, Haejung | Lee, Dong Young | for the KBASE Research Group

Article Type: Research Article

Abstract: Background: Previous studies indicated an association between Alzheimer’s disease (AD) dementia and air particulate matter (PM) with aerodynamic diameter <10μ m (PM10), as well as smaller PM. Limited information, however, is available for the neuropathological links underlying such association. Objective: This study aimed to investigate the relationship between long-term PM10 exposure and in vivo pathologies of AD using multimodal neuroimaging. Methods: The study population consisted of 309 older adults without dementia (191 cognitively normal and 118 mild cognitive impairment individuals), who lived in Republic of Korea. Participants underwent comprehensive clinical assessments, 11 C-Pittsburg compound B …(PiB) positron emission tomography (PET), and magnetic resonance imaging scans. A subset of 78 participants also underwent 18 F-AV-1451 tau PET evaluation. The mean concentration of PM with aerodynamic diameter <10μ m over the past 5 years (PM10mean ) collected from air pollution surveillance stations were matched to each participant’s residence. Results: In this non-demented study population, of which 62% were cognitively normal and 38% were in mild cognitive impairment state, exposure to the highest tertile of PM10mean was associated with increased risk of amyloid-β (Aβ ) positivity (odds ratio 2.19, 95% confidence interval 1.13 to 4.26) even after controlling all potential confounders. In contrast, there was no significant associations between PM10mean exposure and tau accumulation. AD signature cortical thickness and white matter hyperintensity volume were also not associated with PM10mean exposure. Conclusion: The findings suggest that long-term exposure to PM10 may contribute to pathological Aβ deposition. Show more

Keywords: Amyloid-β, cognitively normal, mild cognitive impairment, neurodegeneration, PM10, tau

DOI: 10.3233/JAD-200694

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

Authors: Andreu-Reinón, María Encarnación | Huerta, José María | Gavrila, Diana | Amiano, Pilar | Mar, Javier | Tainta, Mikel | Ardanaz, Eva | Larumbe, Rosa | Navarro, Carmen | Colorado-Yohar, Sandra M. | Navarro-Mateu, Fernando | Chirlaque, María Dolores

Article Type: Research Article

Abstract: Background: Dementia has become a public health priority as the number of cases continues to grow worldwide. Objective: To assess dementia incidence and determinants in the EPIC-Spain Dementia Cohort. Methods: 25,015 participants (57% women) were recruited from three Spanish regions between 1992-1996 and followed-up for over 20 years. Incident cases were ascertained through individual revision of medical records of potential cases. Crude and age-adjusted incidence rates (IR) of dementia and sub-types (Alzheimer’s disease (AD), and non-AD) were calculated by sex. Neelson-Aalen cumulative incidence estimates at 10, 15, and 20 years were obtained for each sex and …age group. Multivariate Royston-Parmar models were used to assess independent determinants. Results: Global IR were higher in women for dementia and AD, and similar by sex for non-AD. IR ranged from 0.09 cases of dementia (95% confidence interval: 0.06–0.13) and 0.05 [0.03–0.09] of AD per 1000 person-years (py) in participants below 60 years, to 23.2 (15.9–33.8) cases of dementia and 14.6 (9.1–33.5) of AD (per 1000 py) in those ≥85 years. Adjusted IR were consistently higher in women than men for overall dementia and AD. Up to 12.5% of women and 9.1% of men 60–65 years-old developed dementia within 20 years. Low education, diabetes, and hyperlipidemia were the main independent predictors of dementia risk, whereas alcohol showed an inverse association. Conclusion: Dementia incidence increased with age and was higher among women, but showed no geographical pattern. Dementia risk was higher among subjects with lower education, not drinking alcohol, and presenting cardiovascular risk factors. Show more

Keywords: Alzheimer’s disease, cohort study, dementia, EPIC-Spain, epidemiology, incidence, risk factors

DOI: 10.3233/JAD-200774

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

Authors: Posada-Duque, Rafael Andrés | Cardona-Gómez, Gloria Patricia

Article Type: Review Article

Abstract: The neurovascular unit (NVU) is responsible for synchronizing the energetic demand, vasodynamic changes, and neurochemical and electrical function of the brain through a closed and interdependent interaction of cell components conforming to brain tissue. In this review, we will focus on cyclin-dependent kinase 5 (CDK5) as a molecular pivot, which plays a crucial role in the healthy function of neurons, astrocytes, and the endothelium and is implicated in the cross-talk of cellular adhesion signaling, ion transmission, and cytoskeletal remodeling, thus allowing the individual and interconnected homeostasis of cerebral parenchyma. Then, we discuss how CDK5 overactivation affects the integrity of the …NVU in Alzheimer’s disease (AD) and cognitive impairment; we emphasize how CDK5 is involved in the excitotoxicity spreading of glutamate and Ca2+ imbalance under acute and chronic injury. Additionally, we present pharmacological and gene therapy strategies for producing partial depletion of CDK5 activity on neurons, astrocytes, or endothelium to recover neuroplasticity and neurotransmission, suggesting that the NVU should be the targeted tissue unit in protective strategies. Finally, we conclude that CDK5 could be effective due to its intervention on astrocytes by its end feet on the endothelium and neurons, acting as an intermediary cell between systemic and central communication in the brain. This review provides integrated guidance regarding the pathogenesis of and potential repair strategies for AD. Show more

Keywords: Alzheimer’s disease, astrocytes, CDK5, endothelium, neuroprotection, neurovascular unit

DOI: 10.3233/JAD-200730

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2020

Authors: Si, Zizhen | Wang, Xidi

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by complex pathological and biological features. Notably, extracellular amyloid-β deposits as senile plaques and intracellular aggregation of hyperphosphorylated tau as neurofibrillary tangles remain the primary premortem criterion for the diagnosis of AD. Currently, there exist no disease-modifying therapies for AD, and many clinical trials have failed to show its benefits for patients. Heme oxygenase 1 (HO-1) is a 32 kDa enzyme, which catalyzes the degradation of cellular heme to free ferrous iron, biliverdin, and carbon monoxide under stressful conditions. Several studies highlight the crucial pathological roles of HO-1 in the molecular processes of …AD. The beneficial roles of HO-1 overexpression in AD brains are widely accepted due to its ability to convert pro-oxidant heme to biliverdin and bilirubin (antioxidants), which promote restoration of a suitable tissue redox microenvironment. However, the intracellular oxidative stress might be amplified by metabolites of HO-1 and exacerbate the progression of AD under certain circumstances. Several lines of evidence have demonstrated that upregulated HO-1 is linked to tauopathies, neuronal damage, and synapse aberrations in AD. Here, we review the aspects of the molecular mechanisms by which HO-1 regulates AD and the latest information on the pathobiology of AD. We further highlight the neuroprotective and neurodystrophic actions of HO-1 and the feasibility of HO-1 as a therapeutic target for AD. Show more

Keywords: Alzheimer’s disease, heme oxygenase 1, neurodystrophic effects, neuroprotective effects

DOI: 10.3233/JAD-200720

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

Authors: Walter, Marlena | Wiltfang, Jens | Vogelgsang, Jonathan

Article Type: Short Communication

Abstract: Previous studies on blood-based biomarkers for Alzheimer’s disease suggest a less invasive blood test might be a valuable screening tool for Alzheimer-specific pathology. Pre-analytical sample storage conditions seem to play an important role on amyloid-β (Aβ) stability, impacting reliability and reproducibility. This study shows that Aβ40 , Aβ42 , and Aβ42/40 levels significantly and early decrease during storage at room temperature in whole blood or plasma. Storing blood samples at 4°C leads to stable Aβ peptide concentrations up to 72 h. In addition, Aβ peptides can be measured in capillary blood with a stable Aβ42/40 ratio up to 72 h …at 4°C. Show more

Keywords: Alzheimer’s disease, amyloid-β , blood collection, blood storage, plasma biomarker

DOI: 10.3233/JAD-200777

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

Authors: Torres-Acosta, Noel | O’Keefe, James H. | O’Keefe, Evan L. | Isaacson, Richard | Small, Gary

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is increasingly prevalent and over 99% of drugs developed for AD have failed in clinical trials. A growing body of literature suggests that potent inhibitors of tumor necrosis factor-α (TNF-α ) have potential to improve cognitive performance. Objective: In this review, we summarize the evidence regarding the potential for TNF-α inhibition to prevent AD and improve cognitive function in people at risk for dementia. Methods: We conducted a literature review in PubMed, screening all articles published before July 7, 2019 related to TNF blocking agents and curcumin (another TNF-α …inhibitor) in the context of AD pathology. The keywords in the search included: AD, dementia, memory, cognition, TNF-α , TNF inhibitors, etanercept, infliximab, adalimumab, golimumab, and curcumin. Results: Three large epidemiology studies reported etanercept treated patients had 60 to 70% lower odds ratio (OR) of developing AD. Two small-randomized control trials (RCTs) demonstrated an improvement in cognitive performance for AD patients treated with etanercept. Studies using animal models of dementia also reported similar findings with TNF blocking agents (etanercept, infliximab, adalimumab, Theracurmin), which appeared to improve cognition. A small human RCT using Theracurmin, a well-absorbed form of curcumin that lowers TNF-α , showed enhanced cognitive performance and decreased brain levels of amyloid-β plaque and tau tangles. Conclusion: TNF-α targeted therapy is a biologically plausible approach to the preservation of cognition, and warrants larger prospective RCTs to further investigate potential benefits in populations at risk of developing AD. Show more

Keywords: Alzheimer’s disease, dementia, inflammation, mild cognitive impairment, tissue necrosis factor-alpha, TNF-α

DOI: 10.3233/JAD-200711

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

Authors: Day, Gregory S. | Long, Allison | Morris, John C.

Article Type: Research Article

Abstract: Background: Age-associated increases in medical complexity, frailty, and cognitive impairment may compromise reliable reporting of medical history. Objective: To evaluate the influence of increasing age and cognitive impairment on concordance between reported history of stroke and cerebral infarction, and reported history of diabetes and elevated hemoglobinA1c in community-dwelling older adults. Methods: The association between participant-specific factors and accurate reporting of cerebral infarction or diabetes was evaluated using multivariable logistic regression in 1,401 participants enrolled in longitudinal studies of memory and aging, including 425 participants with dementia (30.3%). Stroke and diabetes were selected as index variables as …gold standard measures of both were obtained in all participants: magnetic resonance neuroimaging for cerebral infarcts and hemoglobinA1c (≥6.5%) for diabetes. Results: Concordance between reported history of stroke and imaging-confirmed cerebral infarction was low (sensitivity: 17.4%, 8/46; specificity: 97.9%, 799/816). Small infarcts were strongly associated with inaccurate reporting (OR = 265.8; 95% CI: 86.2, 819.4), suggesting that occult/silent infarcts contributed to discordant reporting. Reporting accuracy was higher concerning diabetes (sensitivity: 83.5%, 147/176; specificity: 96.2%, 1100/1143). A history of hypertension (OR = 2.3; 95% CI: 1.3, 4.2), higher hemoglobinA1c (OR = 1.9; 95% CI: 1.5, 2.4), and hemoglobinA1c compatible with impaired glucose tolerance (OR = 3.1; 95% CI 1.8, 5.3) associated with increased odds of discordant reporting. Cognitive impairment and increased age were not independently associated with reliable reporting. Conclusion: Factors beyond advancing age and cognitive impairment appear to drive discordance in reported medical history in older participants. Objective testing for cerebral infarcts or diabetes should be performed when relevant to diagnostic or therapeutic decisions in clinical and research settings. Show more

Keywords: Alzheimer’s disease, cerebral infarct, cognitive impairment, dementia, diabetes, medical history, reporting accuracy, stroke

DOI: 10.3233/JAD-200842

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

Authors: Duarte-Guterman, Paula | Albert, Arianne Y. | Inkster, Amy M. | Barha, Cindy K. | Galea, Liisa A.M. | on behalf of the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOE ɛ 4 allele. The risk of developing AD is also higher in female APOE ɛ 4 carriers in earlier age groups (aged 65–75), and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be influenced by sex. Inflammation is observed in AD and is related to aging, stress, and neuroplasticity, and although studies are scarce, sex differences are noted in inflammation. Objective: The objective of this …study was to investigate underlying physiological inflammatory mechanisms that may help explain why there are sex differences in AD and APOE ɛ 4 carriers. Methods: We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOE ɛ 4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF (N = 279) and plasma (N = 527) markers of stress and inflammation. Results: We found CSF IL-16 and IL-8 levels were significantly lower in female non-carriers of APOE ɛ 4 alleles compared to males, whereas levels were similar between the sexes among carriers of APOE ɛ 4 alleles. Furthermore, females had on average higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males. Carrying APOE ɛ 4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes. Conclusion: Sex differences in inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin. Show more

Keywords: Alzheimer’s disease, APOE genotype, cytokines, inflammation, sex differences

DOI: 10.3233/JAD-200982

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Jackson, Melinda L. | Cavuoto, Marina | Schembri, Rachel | Doré, Vincent | Villemagne, Victor L. | Barnes, Maree | O’Donoghue, Fergal J. | Rowe, Christopher C. | Robinson, Stephen R.

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea (OSA) has been linked to an increase risk of dementia. Few studies have cross-sectionally examined whether clinically-confirmed OSA is associated with a higher brain amyloid burden. Objective: The aim of this study was to compare brain amyloid burden in individuals with untreated OSA and healthy controls, and explore associations between amyloid burden and polysomnographic and subjective measures of sleep, demographics, and mood. Methods: Thirty-four individuals with OSA (mean age 57.5±4.1 y; 19 males) and 12 controls (mean age 58.5±4.2 y; 6 males) underwent a clinical polysomnogram and a 11 C-PiB positron emission …tomography (PET) scan to quantify amyloid burden. Results: Amyloid burden was elevated in the OSA group relative to controls, and was significantly higher in those with severe OSA relative to mild/moderate OSA. Correlation analyses indicated that higher amyloid burden was associated with a higher Non-REM apnea hypopnea index, poorer sleep efficiency, and less time spent in stage N3 sleep, when controlling for age. Conclusion: Severe OSA is associated with a modest elevation of brain amyloid, the significance of which should be further investigated to explore the implications for dementia risk. Show more

Keywords: Hypoxia, neurodegeneration, neuroimaging, polysomnography, sleep

DOI: 10.3233/JAD-200571

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

Authors: Ashby-Mitchell, Kimberly | Willie-Tyndale, Douladel | Eldemire-Shearer, Denise

Article Type: Research Article

Abstract: Background: Dementia has no known cure and age is its strongest predictor. Given that populations in the Caribbean are aging, a focus on policies and programs that reduce the risk of dementia and its risk factors is required. Objective: To estimate the proportion of dementia in the Jamaican setting attributable to key factors. Methods: We analyzed the contribution of five modifiable risk factors to dementia prevalence in Jamaica using a modified Levin’s Attributable Risk formula (low educational attainment, diabetes, smoking status, depression, and physical inactivity). Four sources of data were used: risk factor prevalence was obtained …from the Jamaica Health and Lifestyle Survey, 2008, relative risk data were sourced from published meta-analyses, shared variance among risk factors was determined using cross-sectional data from the Health and Social Status of Older Persons in Jamaica Study. Estimated future prevalence of dementia in Jamaica was sourced from a published ADI/BUPA report which focused on dementia in the Americas. We computed the number of dementia cases attributable to each risk factor and estimated the effect of a reduction in these risk factors on future dementia prevalence. Results: Accounting for the overlapping of risk factors, 34.46% of dementia cases in Jamaica (6548 cases) were attributable to the five risk factors under study. We determined that if each risk factor were to be reduced by 5% –10% per decade from 2010–2050, dementia prevalence could be reduced by up to 14.0%. Conclusion: As the risk factors for dementia are shared with several of the main causes of death in Jamaica, a reduction in risk factors by even 5% can result in considerable public health benefit. Show more

Keywords: Caribbean, dementia, Jamaica, low and middle-income countries, population attributable risk

DOI: 10.3233/JAD-200601

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

Authors: Jang, Hyemin | Kim, Hee Jin | Sim Choe, Yeong | Kim, Soo-Jong | Park, Seongbeom | Kim, Yeshin | Woon Kim, Ko | Hyoung Lyoo, Chul | Cho, Hanna | Hoon Ryu, Young | Choi, Jae Yong | DeCarli, Charles | Na, Duk L. | Won Seo, Sang | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: As Alzheimer’s disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. Objective: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD. Methods: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer’s disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State …Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ /tau and group on CDR-SB/MMSE changes. Results: The frequency of Aβ positivity (45% versus 54.9%, p  = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p  = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p  = 0.013/p  <  0.001) change, and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p  <  0.001 and p  = 0.030) change. Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p  = 0.001) and V/VI (p  = 0.003) not in Braak I/II region (p  = 0.398). Conclusion: The association between Aβ /tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline. Show more

Keywords: Alzheimer’s disease, amyloid, cerebral small vessel diseases, cognitive dysfunction, positron emission tomography, tau, vascular dementia

DOI: 10.3233/JAD-200680

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

Authors: Hauer, Klaus | Schwenk, Michael | Englert, Stefan | Rixt Zijlstra, G.A. | Tuerner, Sabine | Dutzi, Ilona

Article Type: Research Article

Abstract: Background: Match or mismatch of objective physiological and subjectively perceived fall risk may have serious consequences in patients with dementia (PwD) while research is lacking. Objective: To analyze mismatch of objective and subjective fall risk and associated factors in PwD. Method: Cohort study in a geriatric rehabilitation center. Objective and subjective risk of falling were operationalized by Tinetti’s Performance Oriented Mobility Assessment and the Falls Efficacy Scale-International. Four sub-groups according to objective and subjective fall risk were classified. Subgroups were compared for differences in clinical, cognitive, psychological, and behavioral variables. Results: In geriatric rehab …patients with mild to moderate dementia (n  = 173), two-thirds showed a mismatch of subjective versus objective risk of falling, independently associated with previous falls. Underestimation of objective fall risk (37.6%) was determined by lower activity avoidance (OR 0.39), less concerns about falling due to previous falls (OR 0.25), and higher quality of life (OR 1.10), while overestimation (28.9%) was determined by higher rate of support seeking strategies (OR 50.3), activity avoidance (OR 15.2), better executive (OR 21.0) and memory functions (OR 21.5), and lower quality of life (OR.75) in multivariate logistic regression. Conclusion: The majority of patients showed a mismatch between objective and subjective falls risk. Underestimation as well as overestimation of fall risk was associated with specific profiles based on cognitive- and psychological status, falls and fall-related behavioral consequences which should be included in the comprehensive assessment of fall risk, and planning of individualized fall prevention programs for this population. Show more

Keywords: Cognitive impairment, dementia, elderly, fall risk, falls, fear of falling

DOI: 10.3233/JAD-200572

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Cardoso, Remy | Lemos, Carolina | Oliveiros, Bárbara | Rosário Almeida, Maria | Baldeiras, Inês | Fragão Pereira, Cláudia | Santos, Ana | Duro, Diana | Vieira, Daniela | Santana, Isabel | Resende Oliveira, Catarina

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer’s disease (AD) conversion remain controversial. Objective: Evaluate whether TOMM40 poly-T (TOMM40 ′ 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype. Methods: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group …of those that remained stable (MCI-S). Results: TOMM40 ′ 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p  <  0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOE ɛ 4 allele, both the L allele and ɛ 4 allele lost significance in the model (p  >  0.05). We then analyzed the APOE ɛ 4-TOMM40 ′ 523 haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30–14.83) and mean lower times of conversion to AD (p  = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p  = 0.007). Conclusion: This study shows that the APOE ɛ 4-TOMM40 ′ 523 haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction. Show more

Keywords: Age of onset, Alzheimer’s disease, APOE , biomarker, cerebrospinal fluid, haplotype, mild cognitive impairment, poly T, progression, TOMM40

DOI: 10.3233/JAD-200556

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Calderón-Garcidueñas, Lilian | Torres-Jardón, Ricardo | Franco-Lira, Maricela | Kulesza, Randy | González-Maciel, Angélica | Reynoso-Robles, Rafael | Brito-Aguilar, Rafael | García-Arreola, Berenice | Revueltas-Ficachi, Paula | Barrera-Velázquez, Juana Adriana | García-Alonso, Griselda | García-Rojas, Edgar | Mukherjee, Partha S. | Delgado-Chávez, Ricardo

Article Type: Review Article

Abstract: Alzheimer’s and Parkinson’s diseases (AD, PD) have a pediatric and young adult onset in Metropolitan Mexico City (MMC). The SARS-CoV-2 neurotropic RNA virus is triggering neurological complications and deep concern regarding acceleration of neuroinflammatory and neurodegenerative processes already in progress. This review, based on our MMC experience, will discuss two major issues: 1) why residents chronically exposed to air pollution are likely to be more susceptible to SARS-CoV-2 systemic and brain effects and 2) why young people with AD and PD already in progress will accelerate neurodegenerative processes. Secondary mental consequences of social distancing and isolation, fear, financial insecurity, violence, …poor health support, and lack of understanding of the complex crisis are expected in MMC residents infected or free of SARS-CoV-2. MMC residents with pre-SARS-CoV-2 accumulation of misfolded proteins diagnostic of AD and PD and metal-rich, magnetic nanoparticles damaging key neural organelles are an ideal host for neurotrophic SARS-CoV-2 RNA virus invading the body through the same portals damaged by nanoparticles: nasal olfactory epithelium, the gastrointestinal tract, and the alveolar-capillary portal. We urgently need MMC multicenter retrospective-prospective neurological and psychiatric population follow-up and intervention strategies in place in case of acceleration of neurodegenerative processes, increased risk of suicide, and mental disease worsening. Identification of vulnerable populations and continuous effort to lower air pollution ought to be critical steps. Show more

Keywords: ACE2, air pollution, Alzheimer’s disease, COVID 19, depression, nanoparticles, neurotropism, Parkinson’s disease, SARS-CoV-2, suicide

DOI: 10.3233/JAD-200891

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2020

Authors: Saari, Toni | Koivisto, Anne | Hintsa, Taina | Hänninen, Tuomo | Hallikainen, Ilona

Article Type: Review Article

Abstract: Neuropsychiatric symptoms cause a significant burden to individuals with neurocognitive disorders and their families. Insights into the clinical associations, neurobiology, and treatment of these symptoms depend on informant questionnaires, such as the commonly used Neuropsychiatric Inventory (NPI). As with any scale, the utility of the NPI relies on its psychometric properties, but the NPI faces unique challenges related to its skip-question and scoring formats. In this narrative review, we examined the psychometric properties of the NPI in a framework including properties pertinent to construct validation, and health-related outcome measurement in general. We found that aspects such as test-retest and inter-rater …reliability are major strengths of the NPI in addition to its flexible and relatively quick administration. These properties are desired in clinical trials. However, the reported properties appear to cover only some of the generally examined psychometric properties, representing perhaps necessary but insufficient reliability and validity evidence for the NPI. The psychometric data seem to have significant gaps, in part because small sample sizes in the relevant studies have precluded more comprehensive analyses. Regarding construct validity, only one study has examined structural validity with the NPI subquestions. Measurement error was not assessed in the reviewed studies. For future validation, we recommend using data from all subquestions, collecting larger samples, paying specific attention to construct validity and formulating hypotheses a priori . Because the NPI is an outcome measure of interest in clinical trials, examining measurement error could be of practical importance. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, dementia, measurement, neuropsychiatric inventory, neuropsychiatric symptoms, reliability, validity

DOI: 10.3233/JAD-200739

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Cai, Hong-Bin | Fan, Zhen-Zhen | Tian, Ting | Li, Zi-Chao | Zhao, Chon-Chon | Guo, Wen-Ting | Ge, Zhao-Ming

Article Type: Research Article

Abstract: The connection between diabetes and Alzheimer’s disease (AD) is not fully determined. Hyperphosphorylation of tau protein is mediated by binding and stabilization of truncated p25 with cyclin-dependent kinase-5 (CDK5) in AD. We recently showed that diabetes-associated hyperglycemia increased the CDK5 levels to promote development of AD. Here, we examined the underlying mechanisms. Hyperglycemia and glucose intolerance were induced in rats that had received a low dose of streptozotocin (STZ) and a high fat diet (HFD). Compared to the control rats that received no STZ and were fed a normal diet, the STZ + HFD rats exhibited poorer performance in the behavioral test …and showed hyperacetylation of H3K9 histone on the CDK5 promoter, likely resulting from upregulation of a histone acetyltransferase, GCN5. Inhibition of acetylation of H3K9 histone by a specific GCN5 inhibitor, MB3, attenuated activation of CDK5, resulting in decreased tau phosphorylation in rat brain and improved performance of the rats in the behavior test. Thus, these data suggest that diabetes may promote future development of AD through hyperacetylation of H3K9 histone on CDK5 promoter. Show more

Keywords: Alzheimer’s disease, cyclin-dependent kinase-5, diabetes, GCN5, H3K9 hyperacetylation, tau

DOI: 10.3233/JAD-200163

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

Authors: Lakey-Beitia, Johant | Burillo, Andrea M. | La Penna, Giovanni | Hegde, Muralidhar L. | Rao, K.S.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multi factorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-βprotein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing …its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, copper, iron, metal chelation therapy, metalloproteins, polyphenols, zinc

DOI: 10.3233/JAD-200185

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

Authors: Panzarella, Vera | Mauceri, Rodolfo | Baschi, Roberta | Maniscalco, Laura | Campisi, Giuseppina | Monastero, Roberto

Article Type: Research Article

Abstract: Background: The relationship between Alzheimer’s disease (AD) and periodontitis has been recently investigated with heterogenous results. Objective: This study aims to evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabút Aging Project, a community-based cohort study performed in rural community in Sicily, Italy. Methods: A case-control study (20 subjects with AD, 20 with amnestic mild cognitive impairment (aMCI), and 20 controls) was conducted. The protocol included a comprehensive medical and cognitive-behavioral examination. Full-mouth evaluation, microbial analysis of subgingival plaque samples (by RT-PCR analysis), and oral health-related quality …of life (OHR-QoL) were evaluated. Results: The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than for aMCI (p  = 0.009) and controls (p  = 0.001). Furthermore, the “M” component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in aMCI (p  < 0.001) and controls (p  < 0.001). A Poisson regression model revealed that age (p  < 0.001), male gender (p  = 0.001), and AD (p  = 0.001) were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p  = 0.02), and a higher load of Treponema denticola was found in aMCI than with AD (p  = 0.004). OHR-QoL scores did not differ among the groups. Conclusion: The current research suggests that AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum . These data remain to be confirmed in larger population-based cohorts. Show more

Keywords: Alzheimer’s disease, cognitive impairment, epidemiology, oral health, periodontitis, tooth loss

DOI: 10.3233/JAD-200385

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

Authors: Marino Gammazza, Antonella | Restivo, Vincenzo | Baschi, Roberta | Caruso Bavisotto, Celeste | Cefalù, Angelo B. | Accardi, Giulia | Conway de Macario, Everly | Macario, Alberto J.L. | Cappello, Francesco | Monastero, Roberto

Article Type: Research Article

Abstract: Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer’s disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma …levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR = 1.16, 95% CI 1.04–1.30) and controls (OR = 1.12, 95% CI 1.03–1.22), while Hsp70 was significantly higher only in AD (OR = 1.84, 95% CI 1.09–3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52–0.91) and AD (OR = 0.51, 95% CI 0.35–0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression. Show more

Keywords: Alzheimer’s disease, cognitive impairment, Hsp60, Hsp70, Hsp90, molecular chaperones, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-180825

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018