Journal of Alzheimer's Disease - Volume 78, issue 2

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

Article Type: Research Article

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

Keywords: Hypoxia, neurodegeneration, neuroimaging, polysomnography, sleep

DOI: 10.3233/JAD-200571

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 611-617, 2020

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-200711

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 619-626, 2020

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

Article Type: Research Article

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

Keywords: Mild cognitive impairment, APOEɛ4 alleles, genotype, cytokines, CRP, IL-16, IL-8, cortisol, sex differences

DOI: 10.3233/JAD-200982

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 627-641, 2020

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-200842

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 643-652, 2020

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-200506

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 653-671, 2020

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-200156

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 673-681, 2020

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-200306

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 683-697, 2020

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-191320

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 699-709, 2020

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-200507

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 711-719, 2020

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-200132

Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 721-734, 2020