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

Authors: Laugisch, Oliver | Johnen, Andreas | Maldonado, Alejandra | Ehmke, Benjamin | Walter , Bürgin | Olsen, Ingar | Potempa, Jan | Sculean, Anton | Duning, Thomas | Eick, Sigrun

Article Type: Research Article

Abstract: Background: Recent studies suggest a link between periodontitis and Alzheimer’s disease (AD). Objective: Verification of the presence of periodontal pathogens and the intrathecal generation of pathogen-specific antibodies in 20 patients with AD and 20 with other forms of dementia (DEM-noAD). Methods: Clinical periodontal indices were recorded. Cerebrospinal fluid (CSF) was analyzed for total tau protein (T-tau) and amyloid-β (Aβ 1 - 42 ). In serum and CSF, antibody levels against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans , and Treponema species were quantified. The presence of selected bacteria and inflammatory biomarkers were determined in periodontium, serum, and …CSF. Results: In line with diagnoses, CSF-levels of Aβ 1 - 42 were significantly lower in AD than DEM-noAD patients. Periodontal destruction and inflammation were omnipresent with no difference between groups. P. gingivalis , T. forsythia, and Treponema species were detected in more than 50% of subgingival biofilm samples, but neither in serum nor in the CSF. Elevated levels of anti-pathogen antibodies in CSF of 16 patients (7 AD; 9 DEM-noAD) compared to serum highlight a possibility of the intrathecal immune response to pathogens. There was no significant difference in antibodies levels against selected bacteria in CSF and serum between groups. Multivariate regression analysis and general linear models revealed an association of the T-tau level in AD group with both serum levels of anti-P. gingivalis antibodies and MCP-1/CCL-2. Conclusion: Periodontal pathogens may enter the brain and stimulate a local immune response. However, in patients with dementia at the age up to 70 years, periodontal pathogens do not act as a trigger for developing AD. Show more

Keywords: Alzheimer’s disease, dementia, periodontitis, periodontal pathogens, Porphyromonas gingivalis

DOI: 10.3233/JAD-180620

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Trumbore, Conrad N.

Article Type: Research Article

Abstract: Amyloid-β oligomers (Aβ O) have been proposed as neurotoxins in the synaptic dysfunction that precedes Alzheimer’s disease symptoms. Human and animal model studies report that senile plaques contain a halo of Aβ O molecules surrounding these plaques. A far smaller number of oligomers are distributed widely in plaque-free regions. It has been suggested that oligomers migrate from halos to nearby synapses and are incorporated into both pre- and postsynaptic terminals. These two types of oligomers have two different toxicities when extracted and injected in animal models. This paper proposes a shear-energy based explanation for the data in these studies. …Shear hypotheses in the preceding three papers in this series are applied to suggest how the hydrodynamics and resulting shear patterns explain the spatial distribution of both Aβ O types, the apparent synapse loss in the vicinity of plaque particles, and possible reasons for the differing toxicities. A shear-based mechanism is proposed for the preferential migration of locally shear-excited Aβ molecules into the synaptic cleft. It is proposed that high energy laminar shear generated by the forced diversion of interstitial fluid around the flow-impeding plaque particle is responsible for the formation of Aβ Os around the plaque. It is suggested that in plaque-free regions, a different type of Aβ O with different toxicity is generated by lower energy shear flow around synapses, depositing Aβ O within the synapse from either the neuron membrane surface or by prion-like seeding within the synaptic cleft by locally-sheared Aβ molecules near the synapse entry. Show more

Keywords: Amyloid, amyloid-β, oligomers, prion, seeding, shear energy, synapse, synaptic cleft

DOI: 10.3233/JAD-171080

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2018

Authors: Ehrenberg, Alexander J. | Suemoto, Claudia K. | de Paula França Resende, Elisa | Petersen, Cathrine | Leite, Renata Elaine Paraizo | Rodriguez, Roberta Diehl | Ferretti-Rebustini, Renata Eloah de Lucena | You, Michelle | Oh, Jun | Nitrini, Ricardo | Pasqualucci, Carlos Augusto | Jacob-Filho, Wilson | Kramer, Joel H. | Gatchel, Jennifer R. | Grinberg, Lea T.

Article Type: Research Article

Abstract: Clarifying the relationships between neuropsychiatric symptoms and Alzheimer’s disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was …used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes. Show more

Keywords: Alzheimer’s disease, amyloid plaques, anxiety, appetite behavior, depression, neurofibrillary tangles, neuropathology, neuropsychiatry, sleep, tau protein

DOI: 10.3233/JAD-180688

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Zuckerman, Scott L. | Brett, Benjamin L. | Jeckell, Aaron | Yengo-Kahn, Aaron M. | Sills, Allen K. | Solomon, Gary S.

Article Type: Research Article

Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by the presence of abnormally phosphorylated tau protein in the depths of one or more cortical sulci. Controversy over the risk of CTE and neurologic disorders later in life among contact sport athletes has taken hold in the public spotlight, most notably in American football. Players, parents, coaches, and legislators have taken action based on the commonly held notion that contact sports invariably lead to neurodegenerative disorders. However, to fully understand the science behind this assumed association, a critical appraisal of the evidence is warranted. With regards to CTE in sports, …the objectives of the current report are to: 1) describe the history of CTE, 2) review current CTE definitions, 3) critically evaluate the empiric data, divided into all contact sports and exclusively American football, and 4) summarize notable themes for future research. Show more

Keywords: Chronic traumatic encephalopathy, concussion, football, neurodegenerative diseases, sports, traumatic brain injury

DOI: 10.3233/JAD-180218

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2018

Authors: O’Bryant, Sid E. | Zhang, Fan | Johnson, Leigh A. | Hall, James | Edwards, Melissa | Grammas, Paula | Oh, Esther | Lyketsos, Constantine G. | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: To date, the therapeutic paradigm for Alzheimer’s disease (AD) focuses on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. Objective: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. Methods: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. Results: 474 participants with mild-to-moderate AD …were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. Conclusion: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD. Show more

Keywords: Alzheimer’s disease, bioinformatics, biomarkers, clinical trial, inflammation, precision medicine, proteomics

DOI: 10.3233/JAD-180619

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Koychev, Ivan | Galna, Brook | Zetterberg, Henrik | Lawson, Jennifer | Zamboni, Giovanna | Ridha, Basil H. | Rowe, James B. | Thomas, Alan | Howard, Robert | Malhotra, Paresh | Ritchie, Craig | Lovestone, Simon | Rochester, Lynn

Article Type: Research Article

Abstract: Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer’s disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ 42 /Aβ 40 and Aβ 42 /Aβ 38 correlated positively with measures of variability (step time and step length) …in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aβ 40 and Aβ 38 but not Aβ 42 .The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ 40 and Aβ 38 ) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid proteins, gait

DOI: 10.3233/JAD-180622

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2018

Authors: Shukla, Deepika | Mandal, Pravat K. | Ersland, Lars | Renate Grüner, Eli | Tripathi, Manjari | Raghunathan, Partha | Sharma, Ankita | Chaithya, G.R. | Punjabi, Khushboo | Splaine, Christopher

Article Type: Research Article

Abstract: Molecular dynamics simulation and in vitro nuclear magnetic resonance (NMR) studies on glutathione (GSH) indicated existence of conformations (closed and extended). The present work in a multi-center research setting investigates in-depth, analysis of GSH conformers in vivo using a common magnetic resonance spectroscopy (MRS) protocol and signal processing scheme. MEGA-PRESS pulse sequence was applied on healthy subjects using 3T Philips MRI scanner (India) and 3T GE MRI scanner (Norway) using the same experimental parameters (echo time, repetition time, and selective 180° refocusing ON-pulse at 4.40 ppm and 4.56 ppm). All MRS data were processed at one site (NBRC) …using in-house MRS processing toolbox for consistency. We have found that both the GSH closed and extended conformations are present in human brain and the relative proportion of individual conformer peak depends on the specific selection of refocusing ON-pulse position in MEGA-PRESS pulse sequence. Based on experiments with different refocusing and inversion pulse positions, echo time, and voxel size, it is clearly evident that both conformational forms of GSH are present in vivo and can be selectively observed by choosing the specific MEGA-PRESS sequence parameters. The GSH conformer peak positions for the closed GSH (Cys-Hβ ) peak at ∼2.80 ppm and extended GSH (Cys-Hβ ) peak at ∼2.95 ppm remains consistent irrespective of the selective refocusing pulse positions. We report the novel research outcome that in human brain both extended and closed GSH conformers are present and can be detected using the MEGA-PRESS sequence employing the parameters derived from high resolution in vitro NMR studies on GSH. Show more

Keywords: Closed and extended conformation, glutathione, MEGA-PRESS MRS, multi-center

DOI: 10.3233/JAD-180648

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Huan, Tao | Tran, Tran | Zheng, Jiamin | Sapkota, Shraddha | MacDonald, Stuart W. | Camicioli, Richard | Dixon, Roger A. | Li, Liang

Article Type: Research Article

Abstract: Using a non-invasive biofluid (saliva), we apply a powerful metabolomics workflow for unbiased biomarker discovery in Alzheimer’s disease (AD). We profile and differentiate Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD groups. The workflow involves differential chemical isotope labeling liquid chromatography mass spectrometry using dansylation derivatization for in-depth profiling of the amine/phenol submetabolome. The total sample (N  = 109) was divided in to the Discovery Phase (DP) (n  = 82; 35 CN, 25 MCI, 22 AD) and a provisional Validation Phase (VP) (n  = 27; 10 CN, 10 MCI, 7 AD). In DP we detected 6,230 metabolites. Pairwise analyses confirmed biomarkers for …AD versus CN (63), AD versus MCI (47), and MCI versus CN (2). We then determined the top discriminating biomarkers and diagnostic panels. A 3-metabolite panel distinguished AD from CN and MCI (DP and VP: Area Under the Curve [AUC] = 1.000). The MCI and CN groups were best discriminated with a 2-metabolite panel (DP: AUC = 0.779; VP: AUC = 0.889). In addition, using positively confirmed metabolites, we were able to distinguish AD from CN and MCI with good diagnostic performance (AUC > 0.8). Saliva is a promising biofluid for both unbiased and targeted AD biomarker discovery and mechanism detection. Given its wide availability and convenient accessibility, saliva is a biofluid that can promote diversification of global AD biomarker research. Show more

Keywords: Alzheimer’s disease, biomarkers, liquid chromatography mass spectrometry, metabolomics, saliva, Victoria Longitudinal Study

DOI: 10.3233/JAD-180711

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Wang, Shanshan | He, Benhong | Hang, Weijian | Wu, NingHua | Xia, Liangtao | Wang, Xu | Zhang, Qianying | Zhou, Xinwen | Feng, Zuohua | Chen, Qingjie | Chen, Juan

Article Type: Research Article

Abstract: Background: Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes. Objective: The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models. Methods: High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, …and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro . Results: Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3β signaling pathway in T2D rats. In vitro , berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3β in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway. Conclusions: Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3β signaling pathway. Show more

Keywords: Axonopathy, berberine, diabetic encephalopathy, insulin, tau phosphorylation

DOI: 10.3233/JAD-180497

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Bloch, Konstantin | Gil-Ad, Irit | Vanichkin, Alexey | Hornfeld, Shay Henry | Taler, Michal | Dar, Shira | Azarov, Dmitry | Vardi, Pnina | Weizman, Abraham

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ). Objective: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats. Methods: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid …cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays. Results: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found. Conclusions: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions. Show more

Keywords: Alzheimer’s disease, animal models, dementia, obesity, pancreatic islet transplantation

DOI: 10.3233/JAD-180623

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2018