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

Authors: Katherine Blujus, Jenna | Elizabeth Korthauer, Laura | Awe, Elizabeth | Frahmand, Marijam | Driscoll, Ira

Article Type: Research Article

Abstract: Background: It is critical to identify individuals at risk for Alzheimer’s disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE , CLU , CR1 , PICALM , and SORL1 that confer increased risk of AD. Objective: In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal control network (FPN), …and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 –60; N = 123; 74 females). Methods: Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Results: Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (p s <  0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (ps <  0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p  <  0.05). There were no APOE- or PICALM-related differences in any of the networks investigated (ps >  0.05). Conclusion: This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU , CR1 , and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD. Show more

Keywords: Aging, Alzheimer’s disease, middle aged, neuroimaging, single nucleotide polymorphism

DOI: 10.3233/JAD-200444

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

Authors: Xia, Ying | Yassi, Nawaf | Raniga, Parnesh | Bourgeat, Pierrick | Desmond, Patricia | Doecke, James | Ames, David | Laws, Simon M. | Fowler, Christopher | Rainey-Smith, Stephanie R. | Martins, Ralph | Maruff, Paul | Villemagne, Victor L. | Masters, Colin L. | Rowe, Christopher C. | Fripp, Jurgen | Salvado, Olivier | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: Cerebrovascular disease often coexists with Alzheimer’s disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis. Objective: We investigate the prevalence and risk factors for the comorbidity of amyloid-β (Aβ ) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association. Methods: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron …emission tomography and structural magnetic resonance imaging for assessment of Aβ deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aβ and cerebrovascular disease (V) as Aβ –V–, Aβ –V+, Aβ +V–, or Aβ +V+. Results: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aβ load and their comorbidity. Apolipoprotein E ɛ 4 carriage was only associated with Aβ positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aβ and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age. Conclusion: Our observations demonstrate common comorbid condition of Aβ and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aβ and WMH burden, future longitudinal studies are required to further confirm this. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrovascular disease, white matter hyperintensities

DOI: 10.3233/JAD-200419

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

Authors: Asken, Breton M. | Elahi, Fanny M. | La Joie, Renaud | Strom, Amelia | Staffaroni, Adam M. | Lindbergh, Cutter A. | Apple, Alexandra C. | You, Michelle | Weiner-Light, Sophia | Brathaban, Nivetha | Fernandes, Nicole | Karydas, Anna | Wang, Paul | Rojas, Julio C. | Boxer, Adam L. | Miller, Bruce L. | Rabinovici, Gil D. | Kramer, Joel H. | Casaletto, Kaitlin B.

Article Type: Research Article

Abstract: Background: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer’s disease (AD). Objective: To examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum. Methods: We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. …All participants with CDR-SB >  0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity. Results: In both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p  = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p  = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5–4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB >  4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP. Conclusion: The relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages. Show more

Keywords: Alzheimer’s disease, amyloid, astrocyte, biomarker, glial fibrillary acidic protein, plasma

DOI: 10.3233/JAD-200755

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

Authors: Li, Yan | Li, Sha | Xu, Shunjiang | Yu, Hong | Tang, Longmei | Liu, Xiaoyun | Wang, Xuemei | Zhang, Yuanyuan | Zhang, Kaixia | Mi, Shixiong | Chen, Meiqin | Cui, Huixian

Article Type: Research Article

Abstract: Background: Age-related hormone changes play important roles in cognitive decline in older men, and apolipoprotein E ɛ 4 (APOE ɛ 4) is a risk factor for Alzheimer’s disease (AD). Objective: This study aimed to investigate the interactive role of androgen decline and APOE ɛ 4 genotype in the pathogenesis of amnestic mild cognitive impairment (aMCI) and AD. Methods: In total, 576 elderly men over 65 years old from communities in Shijiazhuang were enrolled in this study, including 243 with normal cognition (NC), 271 with aMCI, and 62 with probable AD. Cognitive function was evaluated …with a battery of neuropsychological tests. The serum levels of androgen and gonadotropin were detected by ELISA and chemiluminescence immunoassay. Results: The levels of free testosterone (FT) and dihydrotestosterone (DHT) were lower in the aMCI group (p  <  0.05), and even lower in the AD group (p  <  0.001), but the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were higher in AD group (p  <  0.01), comparing with that in NC or aMCI group. The interaction of lower FT or DHT levels with APOE ɛ 4 had a risk role in global cognitive impairment (p  <  0.05). The area under the curve (AUC) of the ROC curve for predicting aMCI by serum FT levels was 0.745. Conclusion: These results indicated that the interaction of androgen decline and APOE ɛ 4 genotype play a role in aMCI and AD. Serum FT levels have a predictive value for aMCI and might be a potential biomarker for prodromal AD. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, androgen, APOE, gonadotropin, testosterone

DOI: 10.3233/JAD-200233

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

Authors: Squarzoni, Paula | Faria, Daniele de Paula | Yassuda, Mônica Sanches | Porto, Fbio Henrique de Gobbi | Coutinho, Artur Martins | Costa, Naomi Antunes da | Nitrini, Ricardo | Forlenza, Orestes Vicente | Duran, Fbio Luiz de Souza | Brucki, Sonia Maria Dozzi | Buchpiguel, Carlos Alberto | Busatto, Geraldo F.

Article Type: Research Article

Abstract: Background: Studies of elderly subjects using biomarkers that are proxies for Alzheimer’s disease (AD) pathology have the potential to document meaningful relationships between cognitive performance and biomarker changes along the AD continuum. Objective: To document cognitive performance differences across distinct AD stages using a categorization based on the presence of PET-assessed amyloid-β (Aβ) burden and neurodegeneration. Methods: Patients with mild dementia compatible with AD (n  = 38) or amnestic mild cognitive impairment (aMCI; n  = 43) and a cognitively unimpaired group (n  = 27) underwent PET with Pittsburgh compound-B (PiB) assessing Aβ aggregation (A+) and [18 F]FDG-PET assessing neurodegeneration …((N)+). Cognitive performance was assessed with verbal and visual episodic memory tests and the Mini-Mental State Examination. Results: The A+(N)+ subgroup (n  = 32) showed decreased (p  <  0.001) cognitive test scores compared to both A+(N)–(n  = 18) and A–(N)–(n  = 49) subjects, who presented highly similar mean cognitive scores. Despite its modest size (n  = 9), the A–(N)+ subgroup showed lower (p  <  0.043) verbal memory scores relative to A–(N)–subjects, and trend lower (p  = 0.096) scores relative to A+(N)–subjects. Continuous Aβ measures (standard uptake value ratios of PiB uptake) were correlated most significantly with visual memory scores both in the overall sample and when analyses were restricted to dementia or (N)+ subjects, but not in non-dementia or (N)–groups. Conclusion: These results demonstrate that significant Aβ-cognition relationships are highly salient at disease stages involving neurodegeneration. The fact that findings relating Aβ burden to memory performance were detected only at (N)+ stages, together with the similarity of test scores between A+(N)–and A–(N)–subjects, reinforce the view that Aβ-cognition relationships during early AD stages may remain undetectable unless substantially large samples are evaluated. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, cognition, cognitively unimpaired, 18-fluorode oxyglucose positron emission tomographic, Pittsburgh compound-B

DOI: 10.3233/JAD-200758

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

Authors: Huang, Liang-Yu | Hu, He-Ying | Wang, Zuo-Teng | Ma, Ya-Hui | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Several existing studies have reported that occupational factors might play an important part in cognitive function with aging. Objective: We aim to explore the associations between modifiable occupational factors and risk of dementia or mild cognitive impairment (MCI). Methods: Adopting random-effect models, this study conducted primary analyses for all occupational factors and subgroup analyses for the effect of occupation type based on prospective cohort and case-control studies searched from PubMed and EMBASE databases up to March 2020. Results: Among the 38,111 identified literatures, 9 studies on occupation type, 4 studies on work complexity, …and 30 studies on occupational exposure were included. In terms of occupation type, mental work conferred a 44% reduced risk (95% CI = 0.34–0.94, I² = 85.00%, p  <  0.01) for MCI. In terms of work complexity, higher work complexity conferred a 5% reduced risk (95% CI = 0.91–1.00, I² = 57.00%, p  <  0.01) for dementia. In terms of occupational exposure, high strain and passive job in the longest-held job conferred a 1.21- and 1.15-fold excess risk (95% CI = 1.05–1.39 I² = 62.00%, p  <  0.05; 95% CI = 1.05–1.26 I² = 31.00%, p  = 0.23; respectively) of cognitive decline. Besides, magnetic field exposure conferred a 1.26-fold excess risk (95% CI = 1.01–1.57, I² = 69.00%, p  <  0.01) for dementia. Conclusion: Novel prevention strategies based on occupational factors may hold promise against dementia and MCI. Show more

Keywords: Dementia, job strain, meta-analysis, occupation occupational exposure, work complexity

DOI: 10.3233/JAD-200605

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 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: Sandau, Ursula S. | Wiedrick, Jack T. | Smith, Sierra J. | McFarland, Trevor J. | Lusardi, Theresa A. | Lind, Babett | Harrington, Christina A. | Lapidus, Jodi A. | Galasko, Douglas R. | Quinn, Joseph F. | Saugstad, Julie A.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer’s disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). Objective: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. Methods: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group …and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ 4 allele (APOE ɛ 4) genotype and amyloid-β 42 to total tau ratio (Aβ 42 :T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. Results: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ 42 :T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p  = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ 42 :T-Tau was weak. Conclusion: Selected miRNAs combined with Aβ 42 :T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ 42 :T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers. Show more

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, biomarkers, cerebrospinal fluid, microRNA, mild cognitive impairment, tau proteins

DOI: 10.3233/JAD-200396

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

Authors: Alipour, Abolfazl | Mozhdehfarahbakhsh, Azadeh | Nouri, Saba | Petramfar, Peyman | Tahamtan, Mahshid | Kamali, Ali-Mohammad | Rao, K. S. | Nami, Mohammad

Article Type: Research Article

Abstract: Background: A proper explanation for perceptual symptoms in neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease (PD) is still lacking. Objective: This study aimed at investigating the imbalance between ‘bottom-up’ and ‘top-down’ information flow (IF) and processing in PD in relation with visual hallucination symptoms. Methods: Here, we looked at bottom-up and top-down IF markers using resting state electroencephalographic (EEG) data from PD patients analyzed through three different IF measures (direct Directed Transfer Function (dDTF), full frequency Directed Transfer Function (ff-DTF), and renormalized Partial Directed Coherence (rPDC). Results: We observed an increased gamma band …IF and a reduced beta band IF in PD patients compared to healthy controls. Additionally, we noticed a reduced theta band IF in PD patients using dDTF as a measure of IF. By source localizing the EEG activity of the PD patients and healthy controls, we looked at the alterations of IF in the prefrontal cortex of PD patients as well. Conclusion: In line with previous studies, our results suggest that the delicate balance between bottom-up and top-down IF is disrupted in Parkinson’s disease potentially contributing to the cognitive symptoms of PD patients. Show more

Keywords: Alzheimer’s disease, direct directed transfer function, EEG, full frequency directed transfer function, information flow, Parkinson’s disease, renormalized partial directed coherence, visual hallucinations

DOI: 10.3233/JAD-200590

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

Authors: Del Percio, Claudio | Drinkenburg, Wilhelmus | Lopez, Susanna | Pascarelli, Maria Teresa | Lizio, Roberta | Noce, Giuseppe | Ferri, Raffaele | Bastlund, Jesper Frank | Laursen, Bettina | Christensen, Ditte Zerlang | Pedersen, Jan T. | Forloni, Gianluigi | Frasca, Angelisa | Noè, Francesco M. | Fabene, Paolo Francesco | Bertini, Giuseppe | Colavito, Valeria | Bentivoglio, Marina | Kelley, Jonathan | Dix, Sophie | Infarinato, Francesco | Soricelli, Andrea | Stocchi, Fabrizio | Richardson, Jill C. | Babiloni, Claudio | on behalf of PharmaCog Consortium

Article Type: Research Article

Abstract: Background: The European PharmaCog study (http://www.pharmacog.org ) has reported a reduction in delta (1–6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer’s disease (AD) amyloidosis and cognitive deficits. Objective: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study. Methods: Ongoing EEG rhythms were recorded from a …frontoparietal bipolar channel in 29 TASTPM and 58 matched “wild type” C57 mice (range of age: 12–24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions. Results: Compared with the “wild type” group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p  <  0.05). This effect was observed in 3 out of 4 EEG recording units. Conclusion: TASTPM mice were characterized by “poor reactivity” of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus unveiling pros and cons of multicenter preclinical EEG trials in TASTPM mice useful for planning future studies. Show more

Keywords: Active and passive state in wakefulness, Alzheimer’s disease, electroencephalography, TASTPM mice, wild type mice

DOI: 10.3233/JAD-190351

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

Authors: Yun, Yejin | Lee, Sang-Yeon | Hoon Choi, Won | Park, Jong-Chan | Han Lee, Dong | Kim, Yun Kyung | Hoon Lee, Jung | Lee, Jun-Young | Jae Lee, Min | Ho Kim, Young

Article Type: Research Article

Abstract: Background: Although the existence of proteasomes in human blood, termed circulating proteasomes (c-proteasomes), has been reported previously, their origin and pathophysiological functions remain largely unknown. Objective: Given that c-proteasome activity was significantly reduced in Alzheimer’s disease model mice and relatively high frequency of mild cognitive impairment (MCI) is accompanied by chronic tinnitus in aged patients, we examined whether c-proteasome activity in human plasma was associated with cognitive function in patients with chronic tinnitus. Methods: c-Proteasome activity in the plasma of tinnitus patients (N = 56) was measured with fluorogenic reporter substrate, suc-LLVY-AMC. To assess MCI, the Montreal Cognitive …Assessment was conducted with a cut-off score of 22/23. All patients underwent audiological and psychoacoustic analyses. Levels of c-proteasomes, Aβ 42 , and Aβ 40 were measured using ELISA, and their association with c-proteasome activity was evaluated. Results: The activity of circulating proteasomes was significantly lower in patients with chronic tinnitus and MCI (p  = 0.042), whereas activities of other plasma enzymes showed little correlation. In addition, c-proteasome activity was negatively associated with the level of plasma Aβ and was directly dependent on its own concentration in the plasma of patients with chronic tinnitus. Conclusion: Our current work provides a new perspective for understanding the potential relationship between circulating proteasomes in the plasma and cognitive dysfunction, suggesting a novel, non-invasive biomarker in the context of MCI diagnosis. Show more

Keywords: Amyloid-β , biomarker, mild cognitive impairment, plasma, proteasome, tinnitus

DOI: 10.3233/JAD-200728

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

Authors: Blanken, Anna E. | Nation, Daniel A.

Article Type: Research Article

Abstract: Background: Gender differences have been noted in studies linking blood pressure to all-cause dementia, and the two most common forms of dementia: Alzheimer’s disease (AD) and vascular dementia (VaD). However, how gender modifies the relationship between blood pressure and dementia remains unclear. Objective: To review evidence for a gender modifying effect on the link between blood pressure and all-cause dementia. Methods: A systematic review was conducted according to PRISMA guidelines. Sixteen out of 256 reviewed articles met inclusion criteria. Results: For women, higher midlife systolic blood pressure (SBP) and hypertension were both associated with …greater risk of all-cause dementia, AD, and VaD, in six out of seven studies. Two of these studies reported higher midlife SBP/hypertension were associated with greater risk for all-cause dementia in women, but not men. One study reported higher midlife SBP associated with greater AD risk in women, but not men. However, another study reported that midlife hypertension associated with AD risk in men, but not women. No clear gender differences were reported in the relationship between late-life high blood pressure/hypertension with all-cause dementia or AD. Conclusion: Studies rarely, and inconsistently, analyzed or reported gender effects. Therefore, interpretation of available evidence regarding the role of gender in blood pressure associated dementia was difficult. Several studies indicated higher midlife SBP was associated with greater risk of all-cause dementia for women, compared to men. Future studies should evaluate women-specific aging processes that occur in midlife when considering the association between blood pressure and dementia risk. Show more

Keywords: Aging, Alzheimer type, blood pressure, dementia, female, gender, hypertension, neurobiology, sex, systematic review, vascular

DOI: 10.3233/JAD-200245

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-27, 2020

Authors: Henkel, Rebecca | Brendel, Matthias | Paolini, Marco | Brendel, Eva | Beyer, Leonie | Gutzeit, Andreas | Pogarell, Oliver | Rominger, Axel | Blautzik, Janusch

Article Type: Research Article

Abstract: Background: Various reasons may lead to cognitive symptoms in elderly, including the development of cognitive decline and dementia. Often, mixed pathologies such as neurodegeneration and cerebrovascular disease co-exist in these patients. Diagnostic work-up commonly includes imaging modalities such as FDG PET, MRI, and CT, each delivering specific information. Objective: To study the informative value of neuroimaging-based data supposed to reflect neurodegeneration (FDG PET), cerebral small vessel disease (MRI), and cerebral large vessel atherosclerosis (CT) with regard to cognitive performance in patients presenting to our memory clinic. Methods: Non-parametric partial correlations and an ordinal logistic regression model …were run to determine relationships between scores for cortical hypometabolism, white matter hyperintensities, calcified plaque burden, and results from Mini-Mental State Examination (MMSE). The final study group consisted of 162 patients (female: 94; MMSE: 6– 30). Results: Only FDG PET data was linked to and predicted cognitive performance (r(157) = – 0.388, p  <  0.001). Overall, parameters linked to cerebral small and large vessel disease showed no significant association with cognition. Further findings demonstrated a relationship between white matter hyperintensities and FDG PET data (r(157) = 0.230, p  = 0.004). Conclusion: Only FDG PET imaging mirrors cognitive performance, presumably due to the examination’s ability to reflect neurodegeneration and vascular dysfunction, thus capturing a broader spectrum of pathologies. This makes the examination a useful imaging-based diagnostic tool in the work-up of patients presenting to a memory clinic. Parameters of vascular dysfunction alone as depicted by conventional MRI and CT are less adequate in such a situation, most likely because they reflect one pathology complex only. Show more

Keywords: Atherosclerosis, cognitive performance, computed tomography, FDG PET, magnetic resonance imaging, neurodegeneration, small vessel disease

DOI: 10.3233/JAD-200826

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

Authors: Watermeyer, Tam | Marroig, Alejandra | Ritchie, Craig W. | Ritchie, Karen | Blennow, Kaj | Muniz-Terrera, Graciela | on behalf of the EPAD Consortium

Article Type: Research Article

Abstract: Background: Cognitive dispersion, variation in performance across cognitive domains, is posited as a non-invasive and cost-effective marker of early neurodegeneration. Little work has explored associations between cognitive dispersion and Alzheimer’s disease (AD) biomarkers in healthy older adults. Even less is known about the influence or interaction of biomarkers reflecting brain pathophysiology or other risk factors on cognitive dispersion scores. Objective: The main aim of this study was to examine whether higher cognitive dispersion was associated with cerebrospinal fluid (CSF) levels of amyloid-β (Aβ 42 ), total tau (t-tau), phosphorylated tau (p-tau), and amyloid positivity in a …cohort of older adults at various severities of AD. A secondary aim was to explore which AD risk factors were associated with cognitive dispersion scores. Methods: Linear and logistic regression analyses explored the associations between dispersion and CSF levels of Aβ 42 , t-tau, and p-tau and amyloid positivity (Aβ 42  <  1000 pg/ml). Relationships between sociodemographics, APOE ɛ 4 status, family history of dementia, and levels of depression and dispersion were also assessed. Results: Dispersion did not emerge as associated with any of the analytes nor amyloid positivity. Older (β = –0.007, SE = 0.002, p  = 0.001) and less educated (β = –0.009, SE = 0.003, p  = 0.009) individuals showed greater dispersion. Conclusion: Dispersion was not associated with AD pathology, but was associated with age and years of education, highlighting individual differences in cognitive aging. The use of this metric as a screening tool for existing AD pathology is not supported by our analyses. Follow-up work will determine if dispersion scores can predict changes in biomarker levels and/or positivity status longitudinally. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, cognition, risk factors, tau

DOI: 10.3233/JAD-200514

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

Authors: Liu, Yi-Hsuan | Gao, Xiang | Na, Muzi | Kris-Etherton, Penny M. | Mitchell, Diane C. | Jensen, Gordon L.

Article Type: Research Article

Abstract: Background: Diet is an important lifestyle factor that may prevent or slow the onset and progression of neurodegeneration. Some, but not all, recent studies have suggested that adherence to a healthy dietary pattern may be associated with reduced risk of dementia. Objective: In this meta-analysis, we systematically examined the associations between overall dietary patterns, assessed a priori and a posteriori , and risk of dementia. Methods: We systematically searched PubMed, Web of Science, and the Cumulative Index for Nursing and Allied Health databases from January 1, 1981 to September 11, 2019. Prospective studies published in …English were included. Random-effects model was used to calculate the pooled risk ratios and 95% confidence intervals (CIs). Results: Sixteen research articles were identified in the systematic review and 12 research articles including 66,930 participants were further included for the meta-analysis. Adherence to high diet quality or a healthy dietary pattern was significantly associated with lower risk of overall dementia (pooled risk ratio = 0.82; 95% CI: 0.70, 0.95; n  = 12) and Alzheimer’s disease (pooled risk ratio = 0.61; 95% CI: 0.47, 0.79; n  = 6) relative to those with low diet quality or an unhealthy dietary pattern. Subgroup analyses stratified by age, sex, follow-up duration, diet quality assessment approach, study location, and study quality generated similar results. Conclusion: Adherence to a healthy dietary pattern was associated with lower risk of overall dementia. Further randomized controlled trials are needed to provide additional evidence about the role of a healthy diet on the development and progression of dementia. Show more

Keywords: Alzheimer’s disease, dementia, diet quality, dietary pattern

DOI: 10.3233/JAD-200499

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

Authors: Karki, Reagon | Madan, Sumit | Gadiya, Yojana | Domingo-Fernández, Daniel | Kodamullil, Alpha Tom | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Background: Recent studies have suggested comorbid association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) through identification of shared molecular mechanisms. However, the inference is pre-dominantly literature-based and lacks interpretation of pre-disposed genomic variants and transcriptomic measurables. Objective: In this study, we aim to identify shared genetic variants and dysregulated genes in AD and T2DM and explore their functional roles in the comorbidity between the diseases. Methods: The genetic variants for AD and T2DM were retrieved from GWAS catalog, GWAS central, dbSNP, and DisGeNet and subjected to linkage disequilibrium analysis. Next, shared variants were …prioritized using RegulomeDB and Polyphen-2. Afterwards, a knowledge assembly embedding prioritized variants and their corresponding genes was created by mining relevant literature using Biological Expression Language. Finally, coherently perturbed genes from gene expression meta-analysis were mapped to the knowledge assembly to pinpoint biological entities and processes and depict a mechanistic link between AD and T2DM. Results: Our analysis identified four genes (i.e., ABCG1 , COMT , MMP9 , and SOD2 ) that could have dual roles in both AD and T2DM. Using cartoon representation, we have illustrated a set of causal events surrounding these genes which are associated to biological processes such as oxidative stress, insulin resistance, apoptosis and cognition. Conclusion: Our approach of using data as the driving force for unraveling disease etiologies eliminates literature bias and enables identification of novel entities that serve as the bridge between comorbid conditions. Show more

Keywords: Alzheimer’s disease, comorbidity, systems biology, type 2 diabetes mellitus

DOI: 10.3233/JAD-200752

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

Authors: Anstey, Kaarin J. | Peters, Ruth | Zheng, Lidan | Barnes, Deborah E. | Brayne, Carol | Brodaty, Henry | Chalmers, John | Clare, Linda | Dixon, Roger A. | Dodge, Hiroko | Lautenschlager, Nicola T. | Middleton, Laura | Qiu, Chengxuan | Rees, Glenn | Shahar, Suzana | Yaffe, Kristine

Article Type: Article Commentary

Abstract: In the past decade a large body of evidence has accumulated on risk factors for dementia, primarily from Europe and North America. Drawing on recent integrative reviews and a consensus workshop, the International Research Network on Dementia Prevention developed a consensus statement on priorities for future research. Significant gaps in geographical location, representativeness, diversity, duration, mechanisms, and research on combinations of risk factors were identified. Future research to inform dementia risk reduction should fill gaps in the evidence base, take a life-course, multi-domain approach, and inform population health approaches that improve the brain-health of whole communities.

Keywords: Multi-domain, primary prevention, risk factor, risk reduction

DOI: 10.3233/JAD-200674

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

Authors: Wang, Wei | Wei, Cuibai | Quan, Meina | Li, Tingting | Jia, Jianping

Article Type: Research Article

Abstract: Background: Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer’s disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Objective: Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Methods: Male SD rats were administered amyloid-β oligomers (Aβ Os) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and …anti-oxidative stress, was injected intraperitoneally to evaluate the therapeutic effect. Results: The results showed that Aβ Os induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. Conclusion: These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, depression, neuroinflammation, oxidative stress, sulforaphane

DOI: 10.3233/JAD-200397

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

Authors: Harris, Christopher J. | Gray, Nora E. | Caruso, Maya | Hunter, Marguex | Ralle, Martina | Quinn, Joseph F.

Article Type: Research Article

Abstract: Background: Environmental copper has been implicated in the pathogenesis of Alzheimer’s disease based on evidence that: 1) brain copper levels increase with age, 2) copper promotes misfolding and toxicity of amyloid-β in vitro , 3) copper-modulating interventions reduce amyloid pathology in animal models. However, the effect of copper upon non-amyloid Alzheimer’s pathology is relatively under-explored. Objective: To determine if modulation of brain copper level affects brain tau pathology and/or associated cognitive impairment. Methods: We tested the hypothesis that brain copper modulates tau pathology by manipulating brain levels of copper in the PS19 transgenic mouse model …of tau pathology. We treated PS19 and wild-type mice with oral zinc acetate, an established therapy for long term control of excess brain copper, and examined treatment effects upon brain copper, brain tau, NFT-like pathology, and spatial memory. We treated a second cohort of mice with exogenous dietary copper in order to evaluate whether excess environmental copper promotes brain tau pathology. Results: Copper-lowering with oral zinc attenuated spatial memory impairment in female but not male PS19 mice, without a significant effect upon tau pathology. Copper loading increased brain copper, but did not have an effect on brain tau pathology or spatial memory function. Conclusion: These findings suggest that a strategy to lower brain copper may be viable for symptomatic benefit in the setting of tau neuropathology, but unlikely to have robust effects on the underlying pathology. These findings are consistent with dietary or other exogenous copper being unlikely to promote tau pathology. Show more

Keywords: Copper, neurofibrillary tangles, tau, zinc

DOI: 10.3233/JAD-200002

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

Authors: Gu, Yebo | Wu, Zhou | Zeng, Fan | Jiang, Muzhou | Teeling, Jessica L. | Ni, Junjun | Takahashi, Ichiro

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and bone loss are clinically exacerbated. However, the mechanism of exacerbation remains understood. Objective: We tested our hypothesis that periodontitis is involved in the exacerbation, contributing to AD pathologies. Methods: The bone, memory, and inflammation in bone and brain were examined in 12-month-old mice after systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (P g LPS) for 3 consecutive weeks. Results: Compared with control mice, bone loss in tibia (26% decrease) and memory decline (47% decrease) were induced in mice with a positive correlation after exposure to P g LPS …(r  = 0.7378, p  = 0.0011). The IL-6 and IL-17 expression in tibia was negatively correlated with the bone volume/total tissue volume (r  = –0.6619, p  = 0.0052; r  = –0.7129, p  = 0.0019), while that in the cortex was negatively correlated with the memory test latency (r  = –0.7198, p  = 0.0017; p  = 0.0351, r  = –0.5291). Furthermore, the IL-17 expression in microglia was positively correlated with Aβ 42 accumulation in neurons (r  = 0.8635, p  <  0.0001). In cultured MG6 microglia, the P g LPS-increased IL-6 expression was inhibited by a PI3K-specific inhibitor (68% decrease), and that of IL-17 was inhibited by IL-6 antibody (41% decrease). In cultured N2a neurons, conditioned medium from P g LPS-stimulated microglia (MCM) but not P g LPS increased the productions of Aβ PP, CatB, and Aβ 42 , which were significantly inhibited by pre-treatment with IL-17 antibody (67%, 51%, and 41% decrease). Conclusion: These findings demonstrated that chronic systemic exposure to P g LPS simultaneously induces inflammation-dependent bone loss and AD-like pathologies by elevating IL-6 and IL-17 from middle age, suggesting that periodontal bacteria induce exacerbation of bone loss and memory decline, resulting in AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β, bone loss, interleukin-6, interleukin-17, lipopolysaccharide from Porphyromonas gingivalis, memory decline, microglia, systemic inflammation

DOI: 10.3233/JAD-200689

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

Authors: Turró-Garriga, Oriol | Viñas-Díez, Vanesa | Conde-Sala, Josep Lluís | Calvó-Perxas, Laia | Cullell-Juncà, Marta | Mas-Vall-Llosera, Glòria | Flaqué, Margarida | Turon-Estrada, Antoni | Juvinyà-Canal, Dolors | Mioshi, Eneida | Garre-Olmo, Josep

Article Type: Research Article

Abstract: Background: Dementia care is associated with physical, emotional, and monetary impact on the informal carers providing unpaid care. Differences in the personal characteristics of caregivers may help explain the variations in the costs of dementia care. Objective: The aim of this study was to analyze the effect of caregivers’ sense of coherence (SOC) on direct and indirect costs in dementia care. Methods: A cross-sectional study was conducted in community dwelling caregivers of patients with Alzheimer’s disease. Data of healthcare services were obtained from clinical registries, and information was collected from caregivers regarding their use of social …care resources and time spent caregiving. The transformation of all costs into Euros was made assigning a fixed cost of 10.29 € /h and 16.24 € /h for assisting in instrumental and basic activities of daily living, respectively. Caregivers’ SOC was assessed using the Orientation to Life Questionnaire (OLQ-13). Adjusted regression models were developed, with different types of costs as dependent variables. Results: A sample of 147 caregivers was recruited. The mean OLQ-13 score was 73.3 points (SD = 11.6). The regression models showed a small association between caregivers’ SOC and direct costs, mainly linked to the use of social care resources (r2  = 0.429; β = –15.6 € /month), and a greater association between SOC and indirect costs (r2  = 0.562; β = –222.3 € /month). Conclusion: Increasing caregivers’ SOC could reduce dementia care costs by decreasing the use of social care resources and caregiving time. Show more

Keywords: Alzheimer’s disease, caregiver, cost of illness, dementia, direct service cost, healthcare cost, sense of coherence

DOI: 10.3233/JAD-200350

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

Authors: Mold, Matthew John | O’Farrell, Adam | Morris, Benjamin | Exley, Christopher

Article Type: Research Article

Abstract: Background: Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer’s disease (fAD) is an early-onset and aggressive form of Alzheimer’s disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson’s disease, dementia onset is known to follow neurofibrillary tangle deposition. Objective: Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high …level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson’s disease, and epilepsy donors. Methods: Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue. Results: We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell. Conclusion: Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson’s disease. Show more

Keywords: α-synuclein, aluminum in human brain tissue, amyloid-β , epilepsy, familial Alzheimer’s disease, Parkinson’s disease, tau

DOI: 10.3233/JAD-200838

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

Authors: de Oliveira, Jade | Engel, Daiane F. | de Paula, Gabriela C. | dos Santos, Danúbia B. | Lopes, Jadna B. | Farina, Marcelo | Moreira, Eduardo L.G. | de Bem, Andreza F.

Article Type: Research Article

Abstract: Background: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr–/–), a mouse model of familial hypercholesterolemia. Objective: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr–/–mice. Methods: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/–mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi. …Results: A tenfold elevation in plasma cholesterol levels of LDLr–/–mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr–/–mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr–/–mice treated with a hypercholesterolemic diet. The LDLr–/–mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr–/–mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice. Conclusion: Therefore, LDLr–/–mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations. Show more

Keywords: Blood-brain barrier, familial hypercholesterolemia, LDLr–/– mice, memory impairment, mild cognitive impairment, neuroinflammation

DOI: 10.3233/JAD-200541

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

Authors: Stephen, Ruth | Solomon, Alina | Ngandu, Tiia | Levälahti, Esko | Rinne, Juha O. | Kemppainen, Nina | Parkkola, Riitta | Antikainen, Riitta | Strandberg, Timo | Kivipelto, Miia | Soininen, Hilkka | Liu, Yawu | for the FINGER study group

Article Type: Research Article

Abstract: Background: Early pathological changes in white matter microstructure can be studied using the diffusion tensor imaging (DTI). It is not only important to study these subtle pathological changes leading to cognitive decline, but also to ascertain and how an intervention would impact the white matter microstructure and cognition in persons at-risk of dementia. Objectives: To study the impact of a multidomain lifestyle intervention on white matter and cognitive changes during the 2-year Finnish Geriatric Intervention Study to prevent Cognitive Impairment and Disability (FINGER), a randomized controlled trial in at-risk older individuals (age 60–77 years) from the general population. …Methods: This exploratory study consisted of a subsample of 60 FINGER participants. Participants were randomized to either a multidomain intervention (diet, exercise, cognitive training, and vascular risk management, n  = 34) or control group (general health advice, n  = 26). All underwent baseline and 2-year brain DTI. Changes in fractional anisotropy (FA), diffusivity along domain (F1) and non-domain (F2) diffusion orientations, mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and their correlations with cognitive changes during the 2-year multidomain intervention were analyzed. Results: FA decreased, and cognition improved more in the intervention group compared to the control group (p  <  0.05), with no significant intergroup differences for changes in F1, F2, MD, AxD, or RD. The cognitive changes were significantly positively related to FA change, and negatively related to RD change in the control group, but not in the intervention group. Conclusion: The 2-year multidomain FINGER intervention may modulate white matter microstructural alterations. Show more

Keywords: Alzheimer’s disease, dementia, diffusion tensor imaging, randomized controlled trial

DOI: 10.3233/JAD-200423

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

Authors: Pietroboni, Anna M. | Colombi, Annalisa | Carandini, Tiziana | Scarpini, Elio | Galimberti, Daniela | Bozzali, Marco

Article Type: Review Article

Abstract: Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer’s disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-β (Aβ ). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at …the earliest disease stages and prior to the presence of Aβ plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aβ levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aβ levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aβ levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology. Show more

Keywords: Amyloid-β , inflammation, neurodegeneration, white matter damage

DOI: 10.3233/JAD-200868

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

Authors: Bergeron, David | Beauregard, Jean-Mathieu | Jean-Guimond, | Soucy, Jean-Paul | Verret, Louis | Poulin, Stéphane | Matias-Guiu, Jordi A. | Cabrera-Martín, María Nieves | Bouchard, Rémi W. | Laforce Jr , Robert

Article Type: Research Article

Abstract: Background: Hypometabolism of the posterior cingulate cortex (PCC) is an important diagnostic feature of late-onset, amnestic Alzheimer’s disease (AD) measured with 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, it is unclear whether PCC hypometabolism has diagnostic value in young-onset, non-amnestic variants of AD, which exhibit less pathology in the hippocampus and default mode network. Objective: Evaluate the prevalence and diagnostic value of PCC hypometabolism in non-amnestic variants of AD. Methods: We retrospectively identified 60 patients with young-onset, atypical dementia who have undergone a detailed clinical evaluation, FDG-PET, and an amyloid biomarker (amyloid-PET or cerebrospinal fluid analysis). …We quantitatively analyzed regional hypometabolism in 70 regions of interest (ROI) using the MIMneuro® software. Results: Based on a cut-off of z-score < –1.5 for significant PCC hypometabolism, the prevalence of PCC hypometabolism in non-amnestic variants of AD was 65% compared to 28% in clinical variants of frontotemporal dementia (FTD). The ROI with the maximal hypometabolism was the dominant middle temporal gyrus in the language variant of AD (mean z score –2.28), middle occipital gyrus in PCA (–3.24), middle temporal gyrus in frontal AD (–2.70), and angular gyrus in corticobasal syndrome due to AD (–2.31). The PCC was not among the 10 most discriminant regions between non-amnestic variants of AD versus clinical variants of FTD. Conclusion: We conclude that PCC hypometabolism is not a discriminant feature to distinguish non-amnestic variants of AD from clinical variants of FTD—and should be interpreted with caution in patients with young-onset, non-amnestic dementia. Show more

Keywords: Alzheimer’s disease, FDG-PET, non-amnestic variants of AD, primary progressive aphasia, posterior cingulate cortex

DOI: 10.3233/JAD-200567

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

Authors: He, Fan | Tang, James J. | Zhang, Tao | Lin, Junfen | Li, Fudong | Gu, Xue | Chen, Ruoling

Article Type: Research Article

Abstract: Background: The impact of air pollution on cognitive impairment in older people has not been fully understood. It is unclear which air pollutants are the culprit. Objective: We assessed the associations of six air pollutants and air quality index (AQI) with cognitive impairment. Methods: We examined 7,311 participants aged ≥60 years from the ZJMPHS cohort in China. They were interviewed for baseline socio-demographic and disease risk factors in 2014, and re-interviewed in 2015 and 2016, respectively. The presence of cognitive impairment was determined by the Chinese version of the Mini-Mental State Examination. Daily area-level data monitored …for air pollution during 2013-2015 was then examined for associations with cognitive impairment in logistic regression models. Results: Over the two years follow-up, 1,652 participants developed cognitive impairment, of which 917 were severe cases. Continuous air pollution data showed the risk of cognitive impairment increased with exposure to PM2.5 (fully adjusted odds ratio [aOR] 1.04, 95% CI 1.01–1.08), PM10 (1.03, 1.001–1.06), and SO2 (1.04, 1.01–1.08), but not with NO2 , CO, O3 , and AQI. Categorized data analysis for low, middle, and high level exposure demonstrated that the aOR increased with PM2.5 and AQI, somehow with PM10 and CO, but not significantly with SO2 and NO2 , and decreased with O3 . The patterns for these associations with severe cognitive impairment were stronger. Conclusion: Lowering PM2.5 , PM10 , SO2 , and CO level could reduce the risk of cognitive impairment in older Chinese. Strategies to target most important air pollutants should be an integral component of cognitive interventions. Show more

Keywords: Air pollution, air quality index, China, cognitive impairment, cohort study

DOI: 10.3233/JAD-200587

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

Authors: Blazel, Madeleine M. | Lazar, Karen K. | Van Hulle, Carol A. | Ma, Yue | Cole, Aleshia | Spalitta, Alice | Davenport-Sis, Nancy | Bendlin, Barbara B. | Wahoske, Michelle | Illingworth, Chuck | Gleason, Carey E. | Edwards, Dorothy F. | Blazel, Hanna | Asthana, Sanjay | Johnson, Sterling C. | Carlsson, Cynthia M.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) provides insight into the spectrum of Alzheimer’s disease (AD) pathology. While lumbar punctures (LPs) for CSF collection are generally considered safe procedures, many participants remain hesitant to participate in research involving LPs. Objective: To explore factors associated with participant willingness to undergo a research LP at baseline and follow-up research study visit. Methods: We analyzed data from 700 participants with varying cognition (unimpaired, mild cognitive impairment, and dementia) in the Wisconsin Alzheimer’s Disease Research Center. We evaluated the relationship of demographic variables (age, sex, race, ethnicity, and years of education) and clinical …variables (waist-to-hip ratio, body mass index, AD parental history, cognitive diagnosis) on decision to undergo baseline LP1. We evaluated the relationship of prior LP1 experience (procedure success and adverse events) with the decision to undergo follow-up LP2. The strongest predictors were incorporated into regression models. Results: Over half of eligible participants opted into both baseline and follow-up LP. Participants who underwent LP1 had higher mean education than those who declined (p  = 0.020). White participants were more likely to choose to undergo LP1 (p  <  0.001); 33% of African American participants opted in compared to 65% of white participants. Controlling for age, education, and AD parental history, race was the only significant predictor for LP1 participation. Controlling for LP1 mild adverse events, successful LP1 predicted LP2 participation. Conclusion: Race was the most important predictor of baseline LP participation, and successful prior LP was the most important predictor of follow-up LP participation. Show more

Keywords: Biomarkers, community participation, lumbar puncture, research subject recruitment

DOI: 10.3233/JAD-200394

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

Authors: Xu, Hui | Jia, Jianping

Article Type: Research Article

Abstract: Background: The pathogenesis of Alzheimer’s disease (AD) involves various immune-related phenomena; however, the mechanisms underlying these immune phenomena and the potential hub genes involved therein are unclear. An understanding of AD-related immune hub genes and regulatory mechanisms would help develop new immunotherapeutic targets. Objective: The aim of this study was to explore the hub genes and the mechanisms underlying the regulation of competitive endogenous RNA (ceRNA) in immune-related phenomena in AD pathogenesis. Methods: We used the GSE48350 data set from the Gene Expression Omnibus database and identified AD immune-related differentially expressed RNAs (DERNAs). We constructed protein–protein …interaction (PPI) networks for differentially expressed mRNAs and determined the degree for screening hub genes. By determining Pearson’s correlation coefficient and using StarBase, DIANA-LncBase, and Human MicroRNA Disease Database (HMDD), the AD immune-related ceRNA network was generated. Furthermore, we assessed the upregulated and downregulated ceRNA subnetworks to identify key lncRNAs. Results: In total, 552 AD immune-related DERNAs were obtained. Twenty hub genes, including PIK3R1 , B2M , HLA-DPB1 , HLA-DQB1 , PIK3CA , APP , CDC42 , PPBP , C3AR1 , HRAS , PTAFR , RAB37 , FYN , PSMD1 , ACTR10 , HLA-E , ARRB2 , GGH , ALDOA , and VAMP2 were identified on PPI network analysis. Furthermore, upon microRNAs (miRNAs) inhibition, we identified LINC00836 and DCTN1-AS1 as key lncRNAs regulating the aforementioned hub genes. Conclusion: AD-related immune hub genes include B2M , FYN , PIK3R1 , and PIK3CA , and lncRNAs LINC00836 and DCTN1-AS1 potentially contribute to AD immune-related phenomena by regulating AD-related hub genes. Show more

Keywords: Alzheimer’s disease, competitive endogenous RNA, hub genes, immune system

DOI: 10.3233/JAD-200081

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

Authors: Hulme, Bethany | Didikoglu, Altug | Bradburn, Steven | Robinson, Andrew | Canal, Maria | Payton, Antony | Pendleton, Neil | Murgatroyd, Chris

Article Type: Research Article

Abstract: Background: An early symptom of Alzheimer’s disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles. Objective: To investigate if BMAL1 , a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology. Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1 , determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score, and Thal phase, longitudinal changes in …cognition, sleep measurements, and cross-section measures of depressive symptoms (BDI score). Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92) = 2.47, p  = 0.015) and CERAD (t(94) = 2.04, p  = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed, and memory tests, but methylation at CpG1 (r  = 0.20, p  = 0.05) and CpG4 (r  = 0.20, p  = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r  = 0.20 p  = 0.05) and vocabulary (r  = 0.22 p  = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep, and efficiency for any of the CpG sites, CpG3 (B = 0.03, 95% CI = 0.00/0.06, p  = 0.03) and CpG5 (B = 0.04, 95% CI = 0.01,0.07, p  = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = –0.27, 95% CI=0.49/–0.05, p  = 0.02). Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle. Show more

Keywords: Alzheimer’s disease, BMAL1, circadian cycle, cognition, depressive symptoms, sleep quality

DOI: 10.3233/JAD-200634

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

Authors: Ling, Yi | Gu, Qilu | Zhang, Junmei | Gong, Tianyu | Weng, Xiongpeng | Liu, Jiaming | Sun, Jing

Article Type: Research Article

Abstract: Background: Post-stroke comorbid cognitive impairment and depression (PSCCID) is a severe neuropsychiatric complication after acute stroke. Gut microbiota dysbiosis is associated with many psychiatric disorders. Alterations in the composition of gut microbiota may serve as a critical role in patients with PSCCID. Objective: We aimed to characterize the microbial profiles of patients with PSCCID. Method: A total of 175 stroke patients were recruited in the study. The composition of gut bacterial communities of patients was determined by 16S ribosomal RNA Miseq sequencing, and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was used to demonstrate …the functional alterations of gut microbiota. We further identified the characteristic gut microbiota of PSCCID using linear discriminant analysis effect size. Results: Patients with PSCCID exhibited an increased abundance of Proteobacteria , including Gammaproteobacteria , Enterobacteriales , and Enterobacteriaceae , and a decreased abundance of several short-chain fatty acids-producing bacteria compared with non-PSCCID patients. The abundance of Gammaproteobacteria and Enterobacteriaceae showed negative correlations with the MoCA score. Moreover, the Kyoto Encyclopedia of Genes and Genomes results demonstrated the enriched orthologs of glycan biosynthesis and metabolism and decreased orthologs of amino acid metabolism in PSCCID patients. Importantly, the characteristic gut microbiota was identified and achieved an area under the curve of 0.847 between the two groups. Conclusion: In this study, we characterized the gut microbiota of PSCCID patients, and revealed the correlations of the altered gut microbiota with clinical parameters, which took a further step towards non-invasive diagnostic biomarkers for PSCCID from fecal samples. Show more

Keywords: Cognitive impairment, correlation, depression, gut microbiota, ischemic stroke

DOI: 10.3233/JAD-200315

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

Authors: Chae, Soohyun | Park, Jinsick | Soo Byun, Min | Yi, Dahyun | Ho Lee, Jun | Hwan Byeon, Gi | Won Suk, Hye | Choi, Hongyoon | Eun Park, Jee | Young Lee, Dong

Article Type: Research Article

Abstract: Background: The degree of alpha attenuation from eyes-closed (EC) to eyes-open (EO) has been suggested as a neural marker of cognitive health, and its disruption has been reported in patients with clinically defined Alzheimer’s disease (AD) dementia. Objective: We tested if EC-to-EO alpha reactivity was related to cerebral amyloid-β (Aβ ) deposition during the early stage of AD. Methods: Non-demented participants aged ≥55 years who visited the memory clinic between March 2018 and June 2019 (N  = 143; 67.8% female; mean age±standard deviation, 74.0±7.6 years) were included in the analyses. Based on the [18 F]florbetaben positron …emission tomography assessment, the participants were divided into Aβ + (N  = 70) and Aβ - (N  = 73) groups. EEG was recorded during the 7 min EC condition followed by a 3 min EO phase, and a Fourier transform spectral analysis was performed. Results: A significant three-way interaction was detected among Aβ positivity, eye condition, and the laterality factor on alpha-band power after adjusting for age, sex, educational years, global cognition, depression, medication use, and white matter hyperintensities on magnetic resonance imaging (F  = 5.987, p  = 0.016); EC-to-EO alpha reactivity in the left hemisphere was significantly reduced in Aβ + subjects without dementia compared with the others (F  = 3.984, p  = 0.048). Conclusion: Among mild cognitive impairment subjects, alpha reactivity additively contributed to predict cerebral Aβ positivity beyond the clinical predictors, including vascular risks, impaired memory function, and apolipoprotein E ɛ 4. These findings support that EC-to-EO alpha reactivity acts as an early biomarker of cerebral Aβ deposition and is a useful measurement for screening early-stage AD. Show more

Keywords: Aged, alpha rhythms, electroencephalography, eyes-closed resting state, eyes-open resting state

DOI: 10.3233/JAD-200442

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

Authors: de Vent, Nathalie R. | Agelink van Rentergem, Joost A. | Huizenga, Hilde M. | van der Flier, Wiesje M. | Sikkes, Sieske A.M. | Murre, Jaap M.J. | van den Bosch, Karlijn A. | Scheltens, Philip | Schmand, Ben A.

Article Type: Research Article

Abstract: Background: In neuropsychology and neurology, there is no consensus on the definition of abnormal cognition. Objective: To operationally define ‘abnormal cognition’ for optimally predicting progression to dementia in a memory clinic sample, and to test whether multivariate profile analysis of cognitive test results improves this prediction compared to standard clinical evaluation. Methods: We used longitudinal data from 835 non-demented patients of the Amsterdam Dementia Cohort. For 10 cognitive measures at baseline, we determined which number of abnormal tests and which magnitude of score deviations best predicted progression. Results: Predictive ability for progression to dementia …of one, two, and three abnormal test scores out of 10 is highly similar (Cox hazard ratios: 3.7–4.1) provided cut-off values are adapted appropriately. Cut-offs have to be less stringent if the number of abnormal tests required increases: the optimal cut-off is z  < –1.45 when one deviating score is required, z  < –1.15 when two abnormal tests are required, and z  < –0.70 when three abnormal tests are required. The profile analysis has similar predictive ability at the cut-off of p  < 0.22 (hazard ratio 3.8). A likelihood ratio test showed that this analysis improves prediction of progression to dementia when added to standard clinical evaluation (p  < 0.001). Conclusion: Abnormal cognition may be defined as one, two, or three abnormal test scores out of 10 if the magnitude of score deviations is adapted accordingly. An abnormal score profile predicts decline to dementia equally well, and improves the prediction when used complimentary to standard clinical evaluation. Show more

Keywords: Cognition, dementia, mild cognitive impairment, multivariate normative comparison, profile analysis

DOI: 10.3233/JAD-200811

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

Authors: Dai, MingRui | Sun, Yao | Mo, ZengShuo | Feng, XueJian | Fu, Lu | Zhang, Yong | Wu, Jiaxin | Yu, Bin | Zhang, Haihong | Yu, Xianghui | Wu, Hui | Kong, Wei

Article Type: Research Article

Abstract: Background: Adjuvants are important components of vaccines and effectively enhance the immune response of specific antigens. However, the role of adjuvants or combinations of adjuvants in stimulating immunogenicity of the amyloid-β (Aβ) vaccine, as well as molecular mechanisms underlying such stimulation still remain unclear. A previous study of ours developed a norovirus P particle-based active Aβ epitope vaccine, PP-3copy-Aβ1-6-loop123, which stimulates a high titer of Aβ-specific antibodies in mouse Alzheimer’s disease (AD) models. Objective: The most effective and safe adjuvant that maximizes the immunogenicity of our protein vaccine was determined. Methods: We investigated four adjuvants (CpG, …AS02, AS03, and MF59), and combinations of those, for capacity to enhance immunogenicity, and performed transcriptome analysis to explore mechanisms underlying the role of these in AD immunotherapy. Results: Addition of the adjuvant, AS02, remarkably improved the immunogenicity of the PP-3copy-Aβ1-6-loop123 vaccine without triggering an Aβ-specific T-cell response. Combinations of adjuvants, particularly CpG +  AS02 and CpG + AS03, elicited a significantly elevated and prolonged Aβ-specific antibody response. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that a combination of two adjuvants was more effective in activating immune-related pathways, thereby enhancing the immunogenicity of PP-3copy-Aβ1-6-loop123. Conclusion: These findings demonstrated that adjuvants can be used as enhancers in AD protein vaccination, and that a combination of CpG and AS-related adjuvants may be a very effective adjuvant candidate suitable for further clinical trials of the PP-3copy-Aβ1-6-loop123 vaccine. Our studies also revealed potential mechanisms underlying the stimulation of immune response of protein vaccines by adjuvants. Show more

Keywords: Adjuvant, Alzheimer’s disease, amyloid-β, immunogenicity, mechanisms, vaccine

DOI: 10.3233/JAD-200351

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

Authors: Beauchamp, Leah C. | Liu, Xiang M. | Sedjahtera, Amelia | Bogeski, Mirjana | Vella, Laura J. | Bush, Ashley I. | Adlard, Paul A. | Barnham, Kevin J.

Article Type: Research Article

Abstract: Background: Alterations in the methionine cycle and abnormal tau phosphorylation are implicated in many neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. rTg4510 mice express mutant human P301L tau and are a model of tau hyperphosphorylation. The cognitive deficit seen in these animals correlates with a burden of hyperphosphorylated tau and is a model to test therapies aimed at lowering phosphorylated tau. Objective: This study aimed to increase protein phosphatase 2A activity through supplementation of S-adenosylmethionine and analyze the effect on spatial memory and tau in treated animals. Methods: 6-month-old rTg4510 mice were treated with 100 mg/kg …S adenosylmethionine by oral gavage for 3 weeks. Spatial recognition memory was tested in the Y-maze. Alterations to phosphorylated tau and protein phosphatase 2A were explored using immunohistochemistry, western blot, and enzyme-linked immunosorbent assays. Results: Treatment with S-adenosylmethionine increased the Y-maze novel arm exploration time and increased both the expression and activity of protein phosphatase 2A. Furthermore, treatment reduced the number of AT8 positive neurons and reduced the expression of phosphorylated tau (Ser202/Thr205). S-adenosylmethionine contributes to multiple pathways in neuronal homeostasis and neurodegeneration. Conclusion: This study shows that supplementation with S-adenosylmethionine stabilizes the heterotrimeric form of PP2A resulting in an increase the enzymatic activity, a reduced level of pathological tau, and improved cognition. Show more

Keywords: Cognition, phosphatase, phosphorylation, PP2A, S-adenosylmethionine, tau, tauopathy

DOI: 10.3233/JAD-200756

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

Authors: Pisano, Francesca | Caltagirone, Carlo | Satriano, Federica | Perri, Roberta | Fadda, Lucia | Marangolo, Paola

Article Type: Research Article

Abstract: Background: Recently, a growing body of evidence has shown that, from the early stage of impairment, Alzheimer’s patients (AD) present difficulties on a variety of tasks mostly relying on executive functions. These strongly impact their daily life activities causing a severe loss of independency and autonomy. Objective: To evaluate the efficacy of transpinal direct current stimulation (tsDCS) combined with cognitive trainings for improving attentional and executive function abilities in a group of AD patients. Methods: In a randomized-double blind design, sixteen AD patients underwent different cognitive trainings combined with tsDCS. During the treatment, each subject received …tsDCS (20 min, 2 mA) over the thoracic vertebrae (IX-X vertebrae) in two different conditions: 1) anodal, and 2) sham while performing three computerized tasks: alertness, selective attention, and executive functions. Each experimental condition was run in ten consecutive daily sessions over two weeks. Results: After anodal tsDCS, a greater improvement in executive functions compared to sham condition was found. More importantly, the follow-up testing revealed that these effects lasted over 1 month after the intervention and generalized to the different neuropsychological tests administered before, after the treatment and at one month after the end of the intervention. This generalization was present also in the attentional domain. Conclusion: This evidence emphasizes, for the first time, that tsDCS combined with cognitive training results efficacious for AD patients. We hypothesize that enhancing activity into the spinal sensorimotor pathways through stimulation improved cognitive abilities which rely on premotor activity, such as attention and executive functions. Show more

Keywords: Alzheimer’s disease, cognitive training, neuromodulation, transpinal stimulation, tsDCS

DOI: 10.3233/JAD-200695

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

Authors: Mathies, Franziska | Lange, Catharina | Mäurer, Anja | Apostolova, Ivayla | Klutmann, Susanne | Buchert, Ralph

Article Type: Research Article

Abstract: Background: Positron emission tomography (PET) of the brain with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) is widely used for the etiological diagnosis of clinically uncertain cognitive impairment (CUCI). Acute full-blown delirium can cause reversible alterations of FDG uptake that mimic neurodegenerative disease. Objective: This study tested whether delirium in remission affects the performance of FDG PET for differentiation between neurodegenerative and non-neurodegenerative etiology of CUCI. Methods: The study included 88 patients (82.0±5.7 y) with newly detected CUCI during hospitalization in a geriatric unit. Twenty-seven (31%) of the patients were diagnosed with delirium during their current hospital stay, which, however, at time …of enrollment was in remission so that delirium was not considered the primary cause of the CUCI. Cases were categorized as neurodegenerative or non-neurodegenerative etiology based on visual inspection of FDG PET. The diagnosis at clinical follow-up after ≥12 months served as ground truth to evaluate the diagnostic performance of FDG PET. Results: FDG PET was categorized as neurodegenerative in 51 (58%) of the patients. Follow-up after 16±3 months was obtained in 68 (77%) of the patients. The clinical follow-up diagnosis confirmed the FDG PET-based categorization in 60 patients (88%, 4 false negative and 4 false positive cases with respect to detection of neurodegeneration). The fraction of correct PET-based categorization did not differ between patients with delirium in remission and patients without delirium (86% versus 89%, p  = 0.666). Conclusion: Brain FDG PET is useful for the etiological diagnosis of CUCI in hospitalized geriatric patients, as well as in patients with delirium in remission. Show more

Keywords: Alzheimer’s disease, Delirium, dementia, neuroimaging, positron-emission tomography

DOI: 10.3233/JAD-200530

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

Authors: Ghoweri, Adam O. | Gagolewicz, Peter | Frazier, Hilaree N. | Gant, John C. | Andrew, R. David | Bennett, Brian M. | Thibault, Olivier

Article Type: Research Article

Abstract: Background: Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer’s disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear. Objective: Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures …associated with oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2 –/– ) mice, a non-transgenic model of sporadic Alzheimer’s disease. Methods: Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2 –/– mouse. Results: Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2 –/– animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2 –/– animals compared to wild-type. Conclusion: With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aβ, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress. Show more

Keywords: Afterhyperpolarization, aging, calcium dysregulation, electrophysiology, hippocampus, HNE, intracellular, oxidative stress

DOI: 10.3233/JAD-200617

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

Authors: Dutt, Shubir | Li, Yanrong | Mather, Mara | Nation, Daniel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Neuropathological studies have suggested the tau pathology observed in Alzheimer’s disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker-confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia. Objective: The present study examined whether MRI-based brainstem volumes differ among cognitively normal older adults and those with MCI or dementia due to AD and whether preclinical brainstem volumes predict future progression to dementia. Methods: Alzheimer’s Disease Neuroimaging Initiative participants (N = 1,629) underwent baseline MRI scanning with …variable clinical follow-up (6–120 months). Region of interest and voxel-based morphometric methods assessed brainstem volume differences among cognitively normal (n  = 814), MCI (n  = 542), and AD (n  = 273) participants, as well as subsets of cerebrospinal fluid biomarker-confirmed MCI (n  = 203) and AD (n  = 160) participants. Results: MCI and AD cases showed smaller midbrain volumes relative to cognitively normal participants when normalizing to whole brainstem volume, and showed smaller midbrain, locus coeruleus, pons, and whole brainstem volumes when normalizing to total intracranial volume. Cognitively normal individuals who later progressed to AD dementia diagnosis exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and voxel-wise analyses revealed specific volumetric reduction of the locus coeruleus. Conclusion: Findings are consistent with neuropathological observations of early AD-related pathology in brainstem nuclei and further suggest the clinical relevance of brainstem substructural volumes in preclinical and prodromal AD. Show more

Keywords: Alzheimer’s disease, biomarkers, brainstem, cognitive aging, locus coeruleus, magnetic resonance imaging, mild cognitive impairment, neuroimaging

DOI: 10.3233/JAD-200187

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

Authors: Sible, Isabel J. | Nation, Daniel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Elevated blood pressure is linked to cognitive impairment and Alzheimer’s disease (AD) biomarker abnormality. However, blood pressure levels vary over time. Less is known about the role of long-term blood pressure variability in cognitive impairment and AD pathophysiology. Objective: Determine whether long-term blood pressure variability is elevated across the clinical and biomarker spectrum of AD. Methods: Alzheimer’s Disease Neuroimaging Initiative participants (cognitively normal, mild cognitive impairment, AD [n  = 1,421]) underwent baseline exam, including blood pressure measurement at 0, 6, and 12 months. A subset (n  = 318) underwent baseline lumbar puncture to determine cerebrospinal fluid amyloid-β …and phosphorylated tau levels. Clinical groups and biomarker-confirmed AD groups were compared on blood pressure variability over 12 months. Results: Systolic blood pressure variability was elevated in clinically diagnosed AD dementia (VIM: F 2,1195  = 6.657, p  = 0.001, η 2  = 0.01) compared to cognitively normal participants (p  = 0.001), and in mild cognitive impairment relative to cognitively normal participants (p  = 0.01). Findings were maintained in biomarker-confirmed AD (VIM: F 2,850  = 5.216, p  = 0.006, η 2  = 0.01), such that systolic blood pressure variability was elevated in biomarker-confirmed dementia due to AD relative to cognitively normal participants (p  = 0.005) and in biomarker-confirmed mild cognitive impairment due to AD compared to cognitively normal participants (p  = 0.04). Conclusion: Long-term systolic blood pressure variability is elevated in cognitive impairment due to AD. Blood pressure variability may represent an understudied aspect of vascular dysfunction in AD with potential clinical implications. Show more

Keywords: Alzheimer’s disease, amyloid, blood pressure, cognitive dysfunction, tau proteins

DOI: 10.3233/JAD-200221

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

Authors: Song, Ge | Yang, Haiqiang | Shen, Ning | Pham, Phillip | Brown, Breanna | Lin, Xiaoyang | Hong, Yuzhu | Sinu, Paul | Cai, Jianfeng | Li, Xiaopeng | Leon, Michael | Gordon, Marcia | Morgan, David | Zhang, Sai | Cao, Chuanhai

Article Type: Research Article

Abstract: Background: Aging is considered the most important risk factor for Alzheimer’s disease (AD). Recent research supports the theory that immunotherapy targeting the “oligomeric” forms of amyloid-β (Aβ ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ , called AN1792, was suspended due to cases of meningoencephalitis in patients. Objective: To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer Aβ and prevent an autoimmune response. Methods: Double transgenic APPswe /PS1Δ E9 (Tg) and C57BL/6J control mice were used in this study. Cytokine expression …profile detection, characterization of antisera, brain GSK-3β , LC3 expression, and spatial working memory testing before and post-vaccination were obtained. Results: Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type Aβ . The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric Aβ -specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC’s natural immunomodulatory properties. Conclusion: The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody’s specificity for these “oligomeric” Aβ species could provide the opportunity to produce some clinical benefits in AD subjects. Show more

Keywords: Alzheimer’s disease, antibody, dendritic cells, T cell epitope, vaccine

DOI: 10.3233/JAD-200413

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

Authors: Blom, Kim | Koek, Huiberdina L. | Zwartbol, Maarten H.T. | Ghaznawi, Rashid | Kuijf, Hugo J. | Witkamp, Theo D. | Hendrikse, Jeroen | Biessels, Geert Jan | Geerlings, Mirjam I. | on behalf of the UCC-SMART Study Group

Article Type: Research Article

Abstract: Background: Vascular risk factors have been associated with risk of Alzheimer’s disease (AD) and volume loss of the hippocampus, but the associations with subfields of the hippocampus are understudied. Knowing if vascular risk factors contribute to hippocampal subfield atrophy may improve our understanding of vascular contributions to neurodegenerative diseases. Objective: To investigate the associations between age, sex, and vascular risk factors with hippocampal subfields volumes on 7T MRI in older persons without dementia. Methods: From the Medea 7T study, 283 participants (67±9 years, 68% men) without dementia had 7T brain MRI and hippocampal subfield segmentation. Subfields …were automatically segmented on the 3D T2-weighted 7T images with ASHS software. Using linear mixed models, we estimated adjusted associations of age, sex, and vascular risk factors with z-scores of volumes of the entorhinal cortex (ERC), subiculum (SUB), Cornu Ammonis (CA)1, CA2, CA3, CA4, and dentate gyrus (DG), and tail as multivariate correlated outcomes. Results: Increasing age was associated with smaller volumes in all subfields, except CA4/DG. Current smoking was associated with smaller ERC and SUB volumes; moderate alcohol use with smaller CA1 and CA4/DG, obesity with smaller volumes of ERC, SUB, CA2, CA3, and tail; and diabetes mellitus with smaller SUB volume. Sex, former smoking, and hypertension were not associated with subfield volumes. When formally tested, no risk factor affected the subfield volumes differentially. Conclusion: Several vascular risk factors were associated with smaller volumes of specific hippocampal subfields. However, no statistical evidence was found that subfields were differentially affected by these risk factors. Show more

Keywords: Cornu ammonis, dentate gyrus, entorhinal cortex, hippocampal region, hippocampus, magnetic resonance imaging, risk factors

DOI: 10.3233/JAD-200159

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

Authors: Al-Janahi, Eiman | Ponirakis, Georgios | Al Hamad, Hanadi | Vattoth, Surjith | Elsotouhy, Ahmed | Petropoulos, Ioannis N. | Khan, Adnan | Gad, Hoda | Chandran, Mani | Sankaranarayanan, Anoop | Ramadan, Marwan | Elorrabi, Marwa | Gadelseed, Masharig | Tosino, Rhia | Gawhale, Priya V. | Arasn, Anjum | Alobaidi, Maryam | Khan, Shafi | Manikoth, Pravija | Hamdi, Yasmin | Osman, Susan | Nadukkandiyil, Navas | AlSulaiti, Essa | Thodi, Noushad | Almuhannadi, Hamad | Mahfoud, Ziyad R. | Own, Ahmed | Shuaib, Ashfaq | Malik, Rayaz A.

Article Type: Research Article

Abstract: Background: Visual rating of medial temporal lobe atrophy (MTA) is an accepted structural neuroimaging marker of Alzheimer’s disease. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic technique that detects neuronal loss in peripheral and central neurodegenerative disorders. Objective: To determine the diagnostic accuracy of CCM for mild cognitive impairment (MCI) and dementia compared to medial temporal lobe atrophy (MTA) rating on MRI. Methods: Subjects aged 60–85 with no cognitive impairment (NCI), MCI, and dementia based on the ICD-10 criteria were recruited. Subjects underwent cognitive screening, CCM, and MTA rating on MRI. Results: 182 subjects …with NCI (n  = 36), MCI (n  = 80), and dementia (n  = 66), including AD (n  = 19, 28.8%), VaD (n  = 13, 19.7%), and mixed AD (n  = 34, 51.5%) were studied. CCM showed a progressive reduction in corneal nerve fiber density (CNFD, fibers/mm2 ) (32.0±7.5 versus 24.5±9.6 versus 20.8±9.3, p  < 0.0001), branch density (CNBD, branches/mm2 ) (90.9±46.5 versus 59.3±35.7 versus 53.9±38.7, p  < 0.0001), and fiber length (CNFL, mm/mm2 ) (22.9±6.1 versus 17.2±6.5 versus 15.8±7.4, p  < 0.0001) in subjects with MCI and dementia compared to NCI. The area under the ROC curve (95% CI) for the diagnostic accuracy of CNFD, CNBD, CNFL compared to MTA-right and MTA-left for MCI was 78% (67–90%), 82% (72–92%), 86% (77–95%) versus 53% (36–69%) and 40% (25–55%), respectively, and for dementia it was 85% (76–94%), 84% (75–93%), 85% (76–94%) versus 86% (76–96%) and 82% (72–92%), respectively. Conclusion: The diagnostic accuracy of CCM, a non-invasive ophthalmic biomarker of neurodegeneration, was high and comparable with MTA rating for dementia but was superior to MTA rating for MCI. Show more

Keywords: Corneal confocal microscopy, corneal nerve fibers, dementia, medial temporal lobe atrophy, mild cognitive impairment, neuropathology

DOI: 10.3233/JAD-200678

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

Authors: Smith, Patrick J. | Mabe, Stephanie M. | Sherwood, Andrew | Murali Doraiswamy, P. | Welsh-Bohmer, Kathleen A. | Burke, James R. | Kraus, William E. | Lin, Pao-Hwa | Browndyke, Jeffrey N. | Babyak, Michael A. | Hinderliter, Alan L. | Blumenthal, James A.

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated that aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet can improve neurocognition. However, the mechanisms by which lifestyle improves neurocognition have not been widely studied. We examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants from the Exercise and Nutritional Interventions for Neurocognitive Health Enhancement (ENLIGHTEN) trial. Objective: To examine the association between changes in metabolic function and neurocognition among older adults with cognitive impairment, but without dementia (CIND) participating in a comprehensive lifestyle intervention. Methods: ENLIGHTEN participants were randomized …using a 2×2 factorial design to receive AE, DASH, both AE+DASH, or a health education control condition (HE) for six months. Metabolic biomarkers included insulin resistance (homeostatic model assessment [HOMA-IR]), leptin, and insulin-like growth factor (IGF-1); neurotrophic biomarkers included brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF); and inflammatory biomarkers included interleukin-6 (IL-6) and C-Reactive Protein (CRP). Results: Participants included 132 sedentary older adults (mean age = 65 [SD = 7]) with CIND. Results demonstrated that both AE (d  = 0.48, p  = 0.015) and DASH improved metabolic function (d  = 0.37, p  = 0.039), without comparable improvements in neurotrophic or inflammatory biomarkers. Greater improvements in metabolic function, including reduced HOMA-IR (B = –2.3 [–4.3, –0.2], p  = 0.033) and increased IGF-1 (B = 3.4 [1.2, 5.7 ], p  = 0.004), associated with increases in Executive Function. Conclusion: Changes in neurocognition after lifestyle modification are associated with improved metabolic function. Show more

Keywords: Aerobic exercise, CIND, DASH diet, executive function, lifestyle modification, metabolic function, vascular risk factors

DOI: 10.3233/JAD-200374

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

Authors: Vila-Castelar, Clara | Guzmán-Vélez, Edmarie | Pardilla-Delgado, Enmanuelle | Buckley, Rachel | Bocanegra, Yamile | Baena, Ana | Fox-Fuller, Joshua T. | Tirado, Victoria | Munoz, Claudia | Giraldo, Margarita | Acosta-Baena, Natalia | Rios-Romenets, Silvia | Langbaum, Jessica B. | Tariot, Pierre N. | Lopera, Francisco | Reiman, Eric M. | Quiroz, Yakeel T.

Article Type: Research Article

Abstract: Background: Growing evidence suggests that there may be a sex-specific biological risk for Alzheimer’s disease (AD). Individuals with autosomal dominant AD due to a mutation (E280A) in Presenilin-1 (PSEN1 ) are genetically determined to develop early-onset dementia and thus, have few age-related risk factors for AD that are known to vary by sex (i.e., cardiovascular disease, menopause, life expectancy). Objective: Investigate sex differences in markers of cognition and neurodegeneration in autosomal dominant AD. Methods: We conducted a retrospective study in 19 cognitively-unimpaired PSEN1 mutation carriers (age range 20–44; 11 females), 11 symptomatic carriers (age range …42–56; 8 females), and 23 matched non-carriers family members (age range 20–50; 13 females). We examined hippocampal volume ratio, CERAD Total Score, and CERAD Word List (i.e., Learning, Delayed Recall, and Recognition). Mann-Whitney U tests, Spearman correlations and regression models were conducted. Results: There were no differential associations between age, CERAD Total Score, CERAD Word List–Learning, Delayed Recall, Recognition, and hippocampal volume ratio in male and female carriers and non-carriers. Cognitively-unimpaired female carriers showed better CERAD Total scores and CERAD Word List-Learning than cognitively-unimpaired male carriers, despite having similar hippocampal volume ratios. The interaction of sex and hippocampal volume ratio did not predict cognitive performance across groups. Conclusion: Our preliminary findings suggest that cognitively-unimpaired female carriers showed a verbal memory reserve, while, as disease progresses, female carriers did not exhibit a cognitive susceptibility to AD-related neurodegeneration. Future studies with larger samples of autosomal dominant AD are warranted to further understand sex differences in AD-related clinical and pathological markers. Show more

Keywords: Alzheimer’s disease, atrophy, cognition, familial Alzheimer’s disease, memory, sex

DOI: 10.3233/JAD-200723

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

Authors: Van Kolen, Kristof | Malia, Thomas J. | Theunis, Clara | Nanjunda, Rupesh | Teplyakov, Alexey | Ernst, Robin | Wu, Sheng-Jiun | Luo, Jinquan | Borgers, Marianne | Vandermeeren, Marc | Bottelbergs, Astrid | Wintmolders, Cindy | Lacy, Eilyn | Maurin, Hervé | Larsen, Peter | Willems, Roland | Van De Casteele, Tom | Triana-Baltzer, Gallen | Slemmon, Randy | Galpern, Wendy | Trojanowski, John Q. | Sun, Hong | Mercken, Marc H.

Article Type: Research Article

Abstract: Background: As a consequence of the discovery of an extracellular component responsible for the progression of tau pathology, tau immunotherapy is being extensively explored in both preclinical and clinical studies as a disease modifying strategy for the treatment of Alzheimer’s disease. Objective: Describe the characteristics of the anti-phospho (T212/T217) tau selective antibody PT3 and its humanized variant hPT3. Methods: By performing different immunization campaigns, a large collection of antibodies has been generated and prioritized. In depth, in vitro characterization using surface plasmon resonance, phospho-epitope mapping, and X-ray crystallography experiments were performed. Further characterization involved immunohistochemical …staining on mouse- and human postmortem tissue and neutralization of tau seeding by immunodepletion assays. Results and Conclusion: Various in vitro experiments demonstrated a high intrinsic affinity for PT3 and hPT3 for AD brain-derived paired helical filaments but also to non-aggregated phospho (T212/T217) tau. Further functional analyses in cellular and in vivo models of tau seeding demonstrated almost complete depletion of tau seeds in an AD brain homogenate. Ongoing trials will provide the clinical evaluation of the tau spreading hypothesis in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, immunotherapy, monoclonal antibodies, tau protein

DOI: 10.3233/JAD-200544

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

Authors: Osuka, Yosuke | Kojima, Narumi | Sasai, Hiroyuki | Ohara, Yuki | Watanabe, Yutaka | Hirano, Hirohiko | Kim, Hunkyung

Article Type: Research Article

Abstract: Background: Participation in exercise may be useful for dementia prevention; however, the specific exercise types which may best to reduce the risk of developing cognitive decline have remained unidentified in the literature. Objective: To examine the relationships of specific exercise types with the risk of developing cognitive decline in older women. Methods: This 1- to 2-year population-based cohort study included 687 community-dwelling older Japanese women without disability, neurological disease, dementia, or cognitive impairment assessed as <24 points on the Mini-Mental State Examination (MMSE) at the baseline survey. Developing cognitive decline was defined as a decrease of …≥3 points in the participant’s MMSE score during the follow-up. We classified individuals into participation (≥3 months) and non-participation (<3 months) groups for 17 different exercise types. Log-binominal regression analyses were applied to compare risk ratios and confidence intervals of developing cognitive decline between the two groups. Results: Thirty-nine participants (5.7%) developed cognitive decline during the follow-up period. After adjusting for confounders (age, MMSE score, depressive symptoms, body mass index, heart disease, hypertension, diabetes, smoking, low educational level, and the follow-up period in the baseline survey), those who participated in calisthenics demonstrated a significantly lower risk of developing cognitive decline than those who did not participate in calisthenics. No significant relationships between other exercise types and the risk of developing cognitive decline were found. Conclusion: Participation in calisthenics significantly reduced the risk of cognitive decline in community-dwelling older Japanese women, indicating that calisthenics may be a useful type of exercise for promoting dementia prevention. Show more

Keywords: Aging, calisthenics, cognitive decline, dementia

DOI: 10.3233/JAD-200867

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

Authors: Holloway, Olivia G. | King, Anna E. | Ziebell, Jenna M.

Article Type: Research Article

Abstract: Background: Microglia are traditionally described as the immune cells of the brain and have an inflammatory role in Alzheimer’s disease (AD). Microglial morphological and phenotypic shifts in AD have not been fully characterized; however, microglia are often described as either pro- or anti-inflammatory. Objective: To determine microglial if microglial morphology and phenotype changes with disease status. Methods: This study observed morphology through Iba1 immunohistochemistry on tissue sections encompassing the primary motor cortex and somatosensory barrel fields. Immunohistochemistry for pro-inflammatory markers: CD14 and CD40; and anti-inflammatory markers: CD16 and TREM2, was performed at 3, 6, and 12 …months of age which correlated with pre-plaque, onset, and significant plaque load in APP/PS1 brains (n  = 6) and compared to age-matched littermate controls (n  = 6). Results: Microglia demonstrated a defined morphological shift with time. Deramified morphologies increased in the APP/PS1, at both 6 months (p  < 0.0001) and 12 months (p  < 0.0001). At 12 months, there were significantly lower numbers of ramified microglia (p  < 0.001). Results indicated that microglia have a heterogenic marker immunoreactivity as CD16, TREM2, and CD40 were associated with an activated morphology at the same time points. All inflammatory markers were significantly upregulated at 12 months in the APP/PS1 mice (TREM2 (F (2,30)   = 10.75, p  = 0.0003), CD40 (F (2,30)   = 15.86, p  < 0.0001), CD14 (F (2,30)   = 6.84, p  = 0.0036), and CD16 (F (2,30)   = 3.026, p  = 0.0635)). Conclusion: Our data indicate that pro- and anti-inflammatory factors of microglia occur in APP/PS1 mice. Show more

Keywords: Alzheimer’s disease, anti-inflammatory, microglia, morphology, phenotype, pro-inflammatory

DOI: 10.3233/JAD-200098

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

Authors: Olive, Claudia | Ibanez, Laura | Farias, Fabiana H. Geraldo | Wang, Fengxian | Budde, John P. | Norton, Joanne B. | Gentsch, Jen | Morris, John C. | Li, Zeran | Dube, Umber | Del-Aguila, Jorge | Bergmann, Kristy | Bradley, Joseph | Benitez, Bruno A. | Harari, Oscar | Fagan, Anne | Ances, Beau | Cruchaga, Carlos | Fernandez, Maria Victoria

Article Type: Research Article

Abstract: Background: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer’s disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. Objective: In this study, we aim to evaluate the association of rare coding variants in PLCG2 , ABI3 , and TREM2 with LOAD risk and their effect at different time points of the disease. Methods: We used a European American cohort to assess the association of the variants …prior onset (using CSF Aβ 42 , tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). Results: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. Conclusion: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease. Show more

Keywords: ABI3 , endophenotypes, late onset Alzheimer’s disease, PLCG2 , progression, TREM2

DOI: 10.3233/JAD-200019

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

Authors: Bergeron, Michael F. | Landset, Sara | Zhou, Xianbo | Ding, Tao | Khoshgoftaar, Taghi M. | Zhao, Feng | Du, Bo | Chen, Xinjie | Wang, Xuan | Zhong, Lianmei | Liu, Xiaolei | Ashford, J. Wesson

Article Type: Research Article

Abstract: Background: The widespread incidence and prevalence of Alzheimer’s disease and mild cognitive impairment (MCI) has prompted an urgent call for research to validate early detection cognitive screening and assessment. Objective: Our primary research aim was to determine if selected MemTrax performance metrics and relevant demographics and health profile characteristics can be effectively utilized in predictive models developed with machine learning to classify cognitive health (normal versus MCI), as would be indicated by the Montreal Cognitive Assessment (MoCA). Methods: We conducted a cross-sectional study on 259 neurology, memory clinic, and internal medicine adult patients recruited from two …hospitals in China. Each patient was given the Chinese-language MoCA and self-administered the continuous recognition MemTrax online episodic memory test on the same day. Predictive classification models were built using machine learning with 10-fold cross validation, and model performance was measured using Area Under the Receiver Operating Characteristic Curve (AUC). Models were built using two MemTrax performance metrics (percent correct, response time), along with the eight common demographic and personal history features. Results: Comparing the learners across selected combinations of MoCA scores and thresholds, Naïve Bayes was generally the top-performing learner with an overall classification performance of 0.9093. Further, among the top three learners, MemTrax-based classification performance overall was superior using just the top-ranked four features (0.9119) compared to using all 10 common features (0.8999). Conclusion: MemTrax performance can be effectively utilized in a machine learning classification predictive model screening application for detecting early stage cognitive impairment. Show more

Keywords: Aging, Alzheimer’s disease, dementia, mass screening

DOI: 10.3233/JAD-191340

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