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

Authors: Jiang, Yanli | Li, Longfei | Dai, Chun-Ling | Zhou, Ranran | Gong, Cheng-Xin | Iqbal, Khalid | Gu, Jin-Hua | Liu, Fei

Article Type: Research Article

Abstract: Background: Abnormally hyperphosphorylated tau is the major protein of neurofibrillary tangles in Alzheimer’s disease. Insulin activates PI3K-AKT signaling and regulates tau phosphorylation. Impaired brain insulin signaling is involved in Alzheimer’s disease pathogenesis. However, the effect of peripheral insulin on tau phosphorylation is controversial. Objective: In the present study, we determined the effect of peripheral insulin administration on tau phosphorylation in brain. Methods: We intraperitoneally injected a super physiological dose of insulin to mice and analyzed PI3K-AKT signaling and tau phosphorylation in brains by western blots. Results: We found that peripherally administered insulin activated the …PI3K-AKT signaling pathway immediately in the liver, but not in the brain. Tau phosphorylation in the mouse brain was found to be first decreased (15 min) and then increased (30 min and 60 min) after peripheral insulin administration and these changes correlated inversely with body temperature and the level of brain protein O-GlcNAcylation. Maintaining body temperature of mice post peripheral insulin administration prevented the insulin/hypoglycemia-induced tau hyperphosphorylation after peripheral insulin administration. Conclusion: These findings suggest that peripheral insulin can induce tau hyperphosphorylation through both hypothermia and downregulation of brain protein O-GlcNAcylation during hypoglycemia. Show more

Keywords: Alzheimer’s disease, insulin, phosphorylation, PI3K-AKT pathway, tau

DOI: 10.3233/JAD-200147

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

Authors: Amariglio, Rebecca E. | Buckley, Rachel F. | Rabin, Jennifer S. | Papp, Kathryn V. | Quiroz, Yakeel T. | Mormino, Elizabeth C. | Sparks, Kathryn P. | Johnson, Keith A. | Rentz, Dorene M. | Sperling, Reisa A.

Article Type: Research Article

Abstract: Background: Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer’s disease pathological differences. Objective: To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline. Methods: 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, …years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Results: Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ , but remained lower for blacks compared to whites (β = –0.24, p  = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β  = –0.055, p  = 0.025) after adjusting for covariates. Conclusion: Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials. Show more

Keywords: African-American, amyloid, cognitive decline, preclinical Alzheimer’s disease

DOI: 10.3233/JAD-191291

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

Authors: Hyun, Jinshil | Hall, Charles B. | Sliwinski, Martin J. | Katz, Mindy J. | Wang, Cuiling | Ezzati, Ali | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: Engaging in mentally challenging activities may protect against dementia in late life. However, little is known whether the association between mentally challenging activities and dementia risk varies with race/ethnicity. Objective: The current study investigates whether having jobs with higher mental stimulation is differentially associated with a decreased risk of dementia between African Americans (AAs) and non-Hispanic Whites (nHWs). Methods: The sample consisted of 1,079 individuals (66% nHWs, 28% AAs; age = 78.6±5.3) from the longitudinal Einstein Aging Study. Occupation information of each participant was collected retrospectively at baseline and was linked to the substantive complexity of work …score from the Dictionary of Occupational Titles. Cox proportional hazards models were used to evaluate the associations of occupational complexity with risk of dementia. Results: Individuals whose jobs had moderate-to-high levels of complexity, compared to those with the lowest complexity, were at modestly decreased risk for incident dementia. When stratified by race, moderate-to-high levels of occupational complexity were significantly associated with lower risk of developing dementia for AAs (HR = 0.35). When risk of dementia was evaluated based on the combinations of race×occupational complexity, AAs with lowest occupational complexity showed the highest risk of developing dementia, while other combinations exhibited lower risk of developing dementia (HRs = 0.36 0.43). Conclusion: Our results suggest that moderate-to-high levels of complexity at work are associated with a decreased risk of incident dementia in AAs. Understanding the differential effects of mentally challenging occupations across race/ethnicity may suggest important intervention strategies that could mitigate racial disparities in dementia rates. Show more

Keywords: African Americans, dementia, occupations, race, workplace

DOI: 10.3233/JAD-191222

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

Authors: Zhou, Ranran | Hu, Wen | Dai, Chun-Ling | Gong, Cheng-Xin | Iqbal, Khalid | Zhu, Dalong | Liu, Fei

Article Type: Research Article

Abstract: Background: Evidence from clinical studies and basic research has shown a strong correlation between Alzheimer’s disease (AD) and type 2 diabetes. Tau, a neuronal microtubule-associated protein, is hyperphosphorylated and aggregated into neurofibrillary tangles in the AD brain. However, the expression of tau in pancreas is under debate. Objective: We determined the expression of tau in mouse pancreas. Methods: We used western blots, immunoprecipitation, and immunohistochemical staining to analyzed pancreatic expression of tau in mice. Results: We found that neither total tau nor phosphorylated tau was detectable in the mouse pancreas by western blots. Immunostaining …with pan tau antibodies R134d and Tau-5 revealed bright and dense varicosities in the pancreatic islets and the exocrine pancreas. These varicosities were immunoreactive to synapsin 1, a presynaptic marker which can outline autonomic nerve profiles in pancreas, exhibiting complete colocalization with tau. Importantly, endocrine cells in islets did not exhibit specific immunoreactivity to any of pan tau antibodies tested, nor did the exocrine cells. Conclusion: In the mouse pancreas, we found that tau is exclusively expressed in autonomic nerve fibers, but there is no detectable expression in endocrine cells in the islet. Show more

Keywords: Autonomic nerve fibers, islets, pancreas, tau

DOI: 10.3233/JAD-200101

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

Authors: Kawasaki, Aki | Ouanes, Sami | Crippa, Sylvain V. | Popp, Julius

Article Type: Research Article

Abstract: Background: Pathologic changes in cerebral and retinal structures governing the pupillary light reflex occur in Alzheimer’s disease (AD). Analysis of pupillary responses originating from different retinal cells may allow for non-invasive detection of cerebral AD pathology. Objective: This study aimed to quantify the pupil light reflex using a portable chromatic pupillometer in patients with early stage AD and compare their responses to those of a healthy control group. Methods: Participants in this case-control pilot study were recruited from a well-characterized cohort of elderly people participating in a larger prospective study on early AD. Cognitive testing, volumetric …brain imaging, and lumbar puncture were performed in all participants to define two groups: early AD, i.e., cognitively impaired subjects with biomarker-confirmed AD pathology, and control group of subjects with normal cognition and normal CSF biomarker profile. Pupil responses to red and blue light stimuli intended to activate cone photoreceptors and melanopsin ganglion cells were recorded under photopic conditions. Results: Sixteen patients with AD (mean age 77 years) and sixteen controls (mean age 71 years) were tested. Baseline pupil size was significantly smaller in AD patients. Pupillary contraction amplitude to all red and blue lights was also smaller in AD patients but did not reach statistical significance. The post-illumination pupillary response was the same between the two groups. Conclusion: Compared to healthy controls, we found only a smaller resting size of the pupil in patients with early AD. The pupillary dynamics to light stimulation remained relatively preserved. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, dementia, melanopsin ganglion cell, pupil, pupil light reflex

DOI: 10.3233/JAD-200120

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

Authors: VanDusen, Keith W. | Eleswarpu, Sarada | Moretti, Eugene W. | Devinney, Michael J. | Crabtree, Donna M. | Laskowitz, Daniel T. | Woldorff, Marty G. | Roberts, Kenneth C. | Whittle, John | Browndyke, Jeffrey N. | Cooter, Mary | Rockhold, Frank W. | Anakwenze, Oke | Bolognesi, Michael P. | Easley, Mark E. | Ferrandino, Michael N. | Jiranek, William A. | Berger, Miles | MARBLE Study Investigators

Collaborators: Adams, Samuel B. | Amundsen, Cindy L. | Avasarala, Pallavi | Barber, Matthew D. | Berchuck, Andrew | Blazer III, Daniel G. | Brassard, Rachele | Brigman, Brian E. | Christensen, Soren K. | Cox, Mitchel W. | Davidson, Brittany A. | DeOrio, James K. | Erdmann, Detlev | Erickson, Melissa M. | Funk, Bonita L. | Gadsden, Jeffrey | Gage, Mark J. | Gingrich, Jeff R. | Greenup, Rachel A. | Ha, Christine | Habib, Ashraf | Abi Hachem, Ralph | Hall, Ashley E. | Hartwig, Matthew G. | Havrilesky, Laura J. | Heflin, Mitchell T. | Holland, Courtney | Hollenbeck, Scott T. | Hopkins, Thomas J. | Inman, Brant A. | Jang, David W. | Kahmke, Russel R. | Karikari, Isaac | Kawasaki, Amie | Klapper, Jacob A. | Klifto, Christopher S. | Klinger, Rebecca | Knechtle, Stuart J. | Lagoo-Deenadayalan, Sandhya A. | Lee, Walter T. | Levinson, Howard | Lewis, Brian D. | Lidsky, Michael E. | Lipkin, Michael E. | Mantyh, Christopher R. | McDonald, Shelley R. | Migaly, John | Miller, Timothy E. | Mithani, Suhail K. | Mosca, Paul J. | Moul, Judd W. | Novick, Thomas L. | Olson, Steven A. | Pappas, Theodore N. | Park, John J. | Peterson, Andrew C. | Phillips, Brett T. | Polascik, Thomas J. | Potash, Peter | Preminger, Glenn M. | Previs, Rebecca A. | Robertson, Cary N. | Scales Jr, Charles D. | Shah, Kevin N. | Scheri, Randall P. | Siddiqui, Nazema Y. | Smani, Shayan | Southerland, Kevin W. | Stang, Michael T. | Syed, Ayesha | Szydlowska, Alicja | Thacker, Julie K.M. | Terrando, Niccolò | Toulgoat-DuBois, Yanne | Visco, Anthony G. | Weidner, Alison C. | Yanamadala, Mamata | Zani Jr, Sabino

Article Type: Research Article

Abstract: Background: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer’s disease (AD) genetic risk factor APOE4 . APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. Objective: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an …apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. Methods: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive drug or placebo before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. Conclusion: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, Apolipoprotein E4, delirium, inflammation, neurocognitive disorders, surgery

DOI: 10.3233/JAD-191185

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

Authors: Tan, Edwin C.K. | Lexomboon, Duangjai | Häbel, Henrike | Fastbom, Johan | Eriksdotter, Maria | Johnell, Kristina | Sandborgh-Englund, Gunilla

Article Type: Research Article

Abstract: Background: Older adults with dementia often have poor oral health. Chronic use of xerogenic medications may contribute to adverse dental outcomes. Objective: To investigate the impact of xerogenic medication classes on the predicted risk for dental interventions in people with dementia. Methods: This was a population-based cohort study involving 30,955 individuals registered in the Swedish Dementia Registry (SveDem) from 2008 to 2012. Data were linked with other national registers. The exposure was xerogenic medication classes used in the three years prior to dementia diagnosis (baseline). The primary outcome was the composite of number of tooth extractions …and dental restorations over the three-year follow-up period. Secondary outcomes included the number of tooth extractions and number of dental restorations. Poisson regression models were used to estimate the association between the exposure and outcomes. Analyses were adjusted for age, gender, Mini-Mental State Examination, living arrangement, dementia disorder, average number of medications, Charlson’s comorbidity index, number of dental visits, and number of teeth. Results: After adjusting for potential covariates, the use of urological drugs (incidence rate ratio [IRR] 1.16, 95% CI 1.04–1.28), proton pump inhibitors (IRR 1.13, 95% CI 1.04–1.23), and opioids (IRR 1.19, 95% CI 1.06–1.34) were significantly associated with the primary composite outcome. Conclusion: The use of specific classes of xerogenic medications was associated with an increased risk for tooth extractions and restorations in people with dementia. The risks and benefits of xerogenic medications, in the context of oral health, should be carefully assessed in this vulnerable population. Show more

Keywords: Dementia, dental care, longitudinal studies, medication, polypharmacy, registers, tooth loss, xerostomia

DOI: 10.3233/JAD-200148

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

Authors: McKeever, Anna | Paris, Alvar F. | Cullen, James | Hayes, Lawrence | Ritchie, Craig W. | Ritchie, Karen | Waldman, Adam D. | Wells, Katie | Busza, Albert | Carriere, Isabelle | O’Brien, John T. | Su, Li

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) begins decades before the onset of dementia. There is a need to investigate biomarkers of early AD for use in clinical trials and to facilitate early intervention. Objective: We aimed to determine whether changes in hippocampal subfield volumes in healthy middle-aged adults were associated with risk of future dementia. Methods: We included 150 participants from the PREVENT-Dementia cohort, which recruited subjects aged 40–59 with or without a family history of dementia (FHD; included here were 81 with FHD and 69 without). Hippocampal subfield volumes were segmented from high resolution T2-weighted 3T MRI …images taken at baseline and 2-year follow-up. Results: FHD and greater 20 year-risk of dementia due to cardiovascular risk factors were both associated with lower CA1 volume. FHD was also associated with a relative increase in combined CA3, CA4, and dentate gyrus volume between baseline and follow-up. Conclusion: CA1 atrophy may commence as early as middle-age in those with a high risk of future dementia, while increases in CA3, CA4, and dentate gyrus volume may be a response to early AD in the form of inflammation or neurogenesis. Show more

Keywords: Alzheimer’s disease, APOE ɛ4, CA1, CA2, CA3, CA4, Dementia Risk Score, dentate gyrus, family history, pre-clinical

DOI: 10.3233/JAD-200238

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

Authors: Chen, Guanqun | Liu, Chunhua | Yang, Kun | Li, Yuxia | Sheng, Can | Xie, Yunyan | Hu, Xiaochen | Jiang, Jiehui | Han, Ying

Article Type: Research Article

Abstract: Background: Clinical research has demonstrated that brain reserve (BR) could exert positive effects on cognition for patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, the effects of BR on cognition in individuals with subjective cognitive decline (SCD) are not clear. Objective: To examine cross-sectional effects of BR on cognition in SCD populations. Methods: One hundred forty-nine subjects were studied from the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Head circumference was used as a proxy of BR. Cognition was assessed across four domains (memory, executive, language, and general cognitive functions). Multiple linear …regression models were conducted to examine effects of BR on cognitive scores. Furthermore, we addressed the question that whether the degree of self-perception of cognitive decline modified the effect of BR on cognitive performance in SCD subjects. Results: We found a positive effect of BR on language cognition in subjects with SCD. Furthermore, the positive effect of BR on language cognition survived in SCD participants with a low degree of self-perception of cognitive decline while disappeared in SCD participants with a high degree of self-perception of cognitive decline. Conclusion: This study suggests that BR has the potential to delay or slow down cognitive decline in SCD individuals, especially for mild SCD. Show more

Keywords: Alzheimer’s disease, brain reserve, head circumference, subjective cognitive decline, subjective cognitive decline questionnaire

DOI: 10.3233/JAD-200005

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

Authors: Petrazzuoli, Ferdinando | Vestberg, Susanna | Midlöv, Patrik | Thulesius, Hans | Stomrud, Erik | Palmqvist, Sebastian

Article Type: Research Article

Abstract: Background: Differentiating mild cognitive impairment (MCI) from subjective cognitive decline (SCD) is important because of the higher progression rate to dementia for MCI and when considering future disease-modifying drugs that will have treatment indications at the MCI stage. Objective: We examined if the two most widely-used cognitive tests, the Mini-Mental State Examination (MMSE) and clock-drawing test (CDT), and a test of attention/executive function (AQT) accurately can differentiate MCI from SCD. Methods: We included 466 consecutively recruited non-demented patients with cognitive complaints from the BioFINDER study who had been referred to memory clinics, predominantly from primary care. …They were classified as MCI (n  = 258) or SCD (n  = 208) after thorough neuropsychological assessments. The accuracy of MMSE, CDT, and AQT for identifying MCI was examined both in training and validation samples and in the whole population. Results: As a single test, MMSE had the highest accuracy (sensitivity 73%, specificity 60%). The best combination of two tests was MMSE < 27 points or AQT > 91 seconds (sensitivity 56%, specificity 78%), but in logistic regression models, their AUC (0.76) was not significantly better than MMSE alone (AUC 0.75). CDT and AQT performed significantly worse (AUC 0.71; p  < 0.001–0.05); otherwise no differences were seen between any combination of two or three tests. Conclusion: Neither single nor combinations of tests could differentiate MCI from SCD with adequately high accuracy. There is a great need to further develop, validate, and implement accurate screening-tests for primary care to improve accurate identification of MCI among individuals that seek medical care due to cognitive symptoms. Show more

Keywords: AQT, clock drawing test, cognitive screening, diagnostic accuracy, mild cognitive impairment, Mini-Mental State Examination, subjective cognitive decline

DOI: 10.3233/JAD-191191

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