Journal of Alzheimer's Disease - Volume 75, issue 4

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. | Cai, Victor | 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 placebo or drug 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. 75, no. 4, pp. 1319-1328, 2020

Authors: Courault, Pierre | Emery, Stéphane | Bouvard, Sandrine | Liger, François | Chauveau, Fabien | Meyronet, David | Fourier, Anthony | Billard, Thierry | Zimmer, Luc | Lancelot, Sophie

Article Type: Research Article

Abstract: Background: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer’s disease (AD) and associated disorders. Objective: The aim of this study was to investigate the binding of [18 F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages. Methods: Patients were classified according to the “ABC” NIA-AA classification. In vitro binding assays …were performed in postmortem brain tissue from the healthy control (HC; n  = 8) and severe AD (“High”; n  = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n  = 15), “Low” (n  = 18), “Int” (n  = 20), and “High” (n  = 15). Results: In vitro binding assays did not show significant differences for the KD and Bmax parameters between “High” and HC groups. In vitro quantitative autoradiography showed a significant difference between the “High” and HC groups (p  = 0.0025). We also showed a progressive diminution in [18 F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined (“Low”, “Intermediate”, and “High”) (p  = 0.011). Conclusion: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18 F]2FNQ1P demonstrated specific binding to 5-HT6 receptors. Show more

Keywords: 5-HT6 receptor, Alzheimer’s disease, caudate nucleus, [18F]2FNQ1P, specific PET radiotracer

DOI: 10.3233/JAD-191278

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1329-1338, 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 analyze 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. 75, no. 4, pp. 1339-1349, 2020

Authors: Guevarra, Anne Cristine | Ng, Sheng Chun | Saffari, Seyed Ehsan | Wong, Benjamin Yi Xin | Chander, Russell Jude | Ng, Kok Pin | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: Hypertension and white matter hyperintensities (WMH) are mutually associated risk factors for cognitive impairment. However, age may modify the associations between hypertension and WMH, and their links to cognitive impairment. Objective: We evaluated the interaction between age and hypertension on WMH, and the age-stratified associations of hypertension and WMH with cognition. Methods: Key measures include systolic blood pressure (SBP), WMH (modified Fazekas visual ratings of cranial MRI), and the Montreal Cognitive Assessment (MoCA). Participants (N = 488) with prodromal and mild dementia were age-stratified (≤49, 50–59, 60–69,≥70), and considered hypertensive if their SBP≥140 mmHg. The interaction between …age strata and hypertension on WMH, and age-stratified associations of hypertension and WMH with cognition, were evaluated using multiple linear regression analyses. Analyses controlled for other risk factors for WMH and cognitive impairment. Results: Age moderated the association between SBP and WMH. Hypertension was associated with higher WMH only in those aged 60–69, and WMH trends across age bands differed between those with and without hypertension. Finally, WMH and SBP≥140 were independently associated with lower MoCA scores within the 50–59 age band, while WMH alone was associated with poorer MoCA scores in the≥70 age band. Conclusion: In adults with prodromal or mild dementia, hypertension was associated with WMH specifically in the 60–69 age strata. Associations between hypertension and WMH with poorer cognition also differed across age bands. Future studies will be needed to investigate whether blood pressure management to slow cognitive decline by targeting WMH may be age dependent. Show more

Keywords: Age, cerebrovascular disease, cognition, hypertension, white matter hyperintensities

DOI: 10.3233/JAD-191260

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1351-1360, 2020

Authors: Haditsch, Ursula | Roth, Theresa | Rodriguez, Leo | Hancock, Sandy | Cecere, Thomas | Nguyen, Mai | Arastu-Kapur, Shirin | Broce, Sean | Raha, Debasish | Lynch, Casey C. | Holsinger, Leslie J. | Dominy, Stephen S. | Ermini, Florian

Article Type: Research Article

Abstract: Background: Porphyromonas gingivalis (P. gingivalis ) and its gingipain virulence factors have been identified as pathogenic effectors in Alzheimer’s disease (AD). In a recent study we demonstrated the presence of gingipains in over 90% of postmortem AD brains, with gingipains localizing to the cytoplasm of neurons. However, infection of neurons by P. gingivalis has not been previously reported. Objective: To demonstrate intraneuronal P. gingivalis and gingipain expression in vitro after infecting neurons derived from human inducible pluripotent stem cells (iPSC) with P. gingivalis for 24, 48, and 72 h. Methods: Infection was …characterized by transmission electron microscopy, confocal microscopy, and bacterial colony forming unit assays. Gingipain expression was monitored by immunofluorescence and RT-qPCR, and protease activity monitored with activity-based probes. Neurodegenerative endpoints were assessed by immunofluorescence, western blot, and ELISA. Results: Neurons survived the initial infection and showed time dependent, infection induced cell death. P. gingivalis was found free in the cytoplasm or in lysosomes. Infected neurons displayed an accumulation of autophagic vacuoles and multivesicular bodies. Tau protein was strongly degraded, and phosphorylation increased at T231. Over time, the density of presynaptic boutons was decreased. Conclusion: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho-tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches. Show more

Keywords: Alzheimer’s disease, gingipain cysteine endopeptidases, in vitro techniques, multivesicular bodies, Porphyromonas gingivalis , synapses, tau protein

DOI: 10.3233/JAD-200393

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1361-1376, 2020

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. 75, no. 4, pp. 1377-1390, 2020

Authors: Fremont, Rachel | Manoochehri, Masood | Armstrong, Nicole M. | Mattay, Venkata S. | Apud, Jose A. | Tierney, Mary C. | Devanand, D.P. | Gazes, Yunglin | Habeck, Christian | Wassermann, Eric M. | Grafman, Jordan | Huey, Edward D.

Article Type: Research Article

Abstract: Background: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). Objective: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD. Methods: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects …on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI). Results: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p  < 0.01), NPI-Q total scores (p  = 0.04), and CGI total scores (p  = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p  = 0.078). Conclusions: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted. Show more

Keywords: COMT, dopamine, frontotemporal dementia, tolcapone, treatment, NCT00604591

DOI: 10.3233/JAD-191265

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1391-1403, 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. 75, no. 4, pp. 1405-1416, 2020

Authors: Kramarz, Barbara | Huntley, Rachael P. | Rodríguez-López, Milagros | Roncaglia, Paola | Saverimuttu, Shirin C.C. | Parkinson, Helen | Bandopadhyay, Rina | Martin, Maria-Jesus | Orchard, Sandra | Hooper, Nigel M. | Brough, David | Lovering, Ruth C.

Article Type: Research Article

Abstract: Background: Gene Ontology (GO) is a major bioinformatic resource used for analysis of large biomedical datasets, for example from genome-wide association studies, applied universally across biological fields, including Alzheimer’s disease (AD) research. Objective: We aim to demonstrate the applicability of GO for interpretation of AD datasets to improve the understanding of the underlying molecular disease mechanisms, including the involvement of inflammatory pathways and dysregulated microRNAs (miRs). Methods: We have undertaken a systematic full article GO annotation approach focused on microglial proteins implicated in AD and the miRs regulating their expression. PANTHER was used for enrichment analysis …of previously published AD data. Cytoscape was used for visualizing and analyzing miR-target interactions captured from published experimental evidence. Results: We contributed 3,084 new annotations for 494 entities, i.e., on average six new annotations per entity. This included a total of 1,352 annotations for 40 prioritized microglial proteins implicated in AD and 66 miRs regulating their expression, yielding an average of twelve annotations per prioritized entity. The updated GO resource was then used to re-analyze previously published data. The re-analysis showed novel processes associated with AD-related genes, not identified in the original study, such as ‘gliogenesis ’, ‘regulation of neuron projection development ’, or ‘response to cytokine ’, demonstrating enhanced applicability of GO for neuroscience research. Conclusions: This study highlights ongoing development of the neurobiological aspects of GO and demonstrates the value of biocuration activities in the area, thus helping to delineate the molecular bases of AD to aid the development of diagnostic tools and treatments. Show more

Keywords: Alzheimer’s disease, Cytoscape network analysis, Gene Ontology, microglia, neuroinflammation, PANTHER

DOI: 10.3233/JAD-200207

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1417-1435, 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. 75, no. 4, pp. 1437-1446, 2020