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