Journal of Alzheimer's Disease - Volume 66, issue 1

Authors: Evered, L. | Silbert, B. | Knopman, D.S. | Scott, D.A. | DeKosky, S.T. | Rasmussen, L.S. | Oh, E.S. | Crosby, G. | Berger, M. | Eckenhoff, R.G. | The Nomenclature Consensus Working Group

Article Type: Research Article

Abstract: Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into …these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that ‘perioperative neurocognitive disorders’ be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder ); any form of acute event (postoperative delirium ) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery ) and up to 12 months (postoperative neurocognitive disorder ). Show more

Keywords: Cognition disorders, delirium, neurocognitive disorders, postoperative complications

DOI: 10.3233/JAD-189004

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 1-10, 2018

Authors: Grizzanti, John | Corrigan, Rachel | Casadesus, Gemma

Article Type: Review Article

Abstract: Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer’s disease (AD). Interestingly, both AD and T2D have similar characteristics including amyloid peptide aggregation, decreased metabolism, and increased oxidative stress and inflammation. Despite their prevalence, therapies for these diseases are limited. To date, most therapies for AD have targeted amyloid-β or tau. Unfortunately, most of these clinical trials have been largely unsuccessful, creating a crucial need for novel therapies. A number of studies have shown that metabolic hormone therapies are effective at ameliorating high blood glucose levels in diabetics as well as improving …cognitive function in AD and mild cognitive impairment patients. Pramlintide, a synthetic analogue of the pancreatic hormone amylin, has been developed and used for years now as a treatment for both type I diabetes and T2D due to the loss of β-islet cells responsible for producing amylin. Importantly, recent data demonstrates its potential therapeutic role for AD as well. This review aims at addressing parallels between T2D and AD at a pathological and functional level, focusing on amylin signaling as a key, overlapping mediator in both diseases. The potential therapeutic use of this hormone to treat AD will also be explored from a mechanistic viewpoint. Show more

Keywords: Alzheimer’s disease, amylin, cognition, pramlintide, type II diabetes

DOI: 10.3233/JAD-180433

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 11-23, 2018

Authors: Doig, Andrew J.

Article Type: Review Article

Abstract: The dominant model for Alzheimer’s disease (AD) is the amyloid cascade hypothesis, in which the accumulation of excess amyloid-β (Aβ) leads to inflammation, excess glutamate and intracellular calcium, oxidative stress, tau hyperphosphorylation and tangle formation, neuronal loss, and ultimately dementia. In a cascade, AD proceeds in a unidirectional fashion, with events only affecting downstream processes. Compelling evidence now exists for the presence of positive feedback loops in AD, however, involving oxidative stress, inflammation, glutamate, calcium, and tau. The pathological state of AD is thus a system of positive feedback loops, leading to amplification of the initial perturbation, rather than a …linear cascade. Drugs may therefore be effective by targeting numerous points within the loops, rather than concentrating on upstream processes. Anti-inflammatories and anti-oxidants may be especially valuable, since these processes are involved in many loops and hence would affect numerous processes in AD. Show more

Keywords: Aggregation, amyloid, amyloid-β protein precursor, directed acyclic graph, drug discovery, peptide, systems biology

DOI: 10.3233/JAD-180583

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 25-36, 2018

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

Article Type: Review 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. 66, no. 1, pp. 37-55, 2018

Authors: Trumbore, Conrad N.

Article Type: Research Article

Abstract: Amyloid-β oligomers (AβO) 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 AβO 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 AβO 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 AβOs around the plaque. It is suggested that in plaque-free regions, a different type of AβO with different toxicity is generated by lower energy shear flow around synapses, depositing AβO 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. 66, no. 1, pp. 57-73, 2018

Authors: Emmerzaal, Tim L. | Rodenburg, Richard J. | Tanila, Heikki | Verweij, Vivienne | Kiliaan, Amanda J. | Kozicz, Tamas

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) is a severe neurodegenerative disorder for which the exact etiology is largely unknown. An increasingly recognized and investigated notion is the pathogenic role of mitochondrial dysfunction in AD. We assessed mitochondrial oxidative-phosphorylation (OXPHOS) enzyme activities in the APPswe/PS1ΔE9 mouse model from 4.5 to 14 months of age. We show an age-dependent decrease in mitochondrial complex-II activity starting at 9 months in APP/PS1 mice. Other enzymes of the OXPHOS do not show any alterations. Since amyloid-β (Aβ) plaques are already present from 4 months of age, mitochondrial dysfunction likely occurs downstream of Aβ pathology in this mouse …model. Show more

Keywords: Alzheimer’s disease, amyloid beta-peptides, electron transport complex II, electron transport complex IV, mice, mitochondria

DOI: 10.3233/JAD-180337

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 75-82, 2018

Authors: Mallo, Sabela C. | Ismail, Zahinoor | Pereiro, Arturo X. | Facal, David | Lojo-Seoane, Cristina | Campos-Magdaleno, María | Juncos-Rabadán, Onésimo

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are non-cognitive, behavioral, or psychiatric symptoms, common in mild cognitive impairment (MCI) and associated with a higher risk of dementia. Mild behavioral impairment (MBI) is a validated diagnostic entity, that describes the emergence of later life NPS in pre-dementia states. The Mild Behavioral Impairment Checklist (MBI-C) is the first measure developed to assess MBI. Objective: To estimate the prevalence of MBI in people with MCI and to study the score distribution, sensitivity, specificity, diagnostic utility of the MBI-C, and its correlations with neuropsychological tests. Methods: One hundred eleven MCI participants were evaluated …with the Questionnaire for Subjective Memory Complaints (QSMC), Mini-Mental State Examination, Cambridge Cognitive Assessment-Revised, Neuropsychiatric Inventory-Questionnaire (NPI-Q), Geriatric Depression Scale-15 items (GDS-15), Lawton and Brody Index, and the MBI-C, which was administered by phone to participants’ informants. Descriptive, logistic regression, ROC curve, and bivariate correlations analyses were performed. Results: MBI diagnosis prevalence was 14.2%. The total MBI-C score differentiated people with MBI at a cutoff-point of 6.5, optimizing sensitivity and specificity. MBI-C total score correlated positively with NPI-Q, QSMC, GDS-15, and Lawton and Brody Index. Conclusion: The total MBI-C score, obtained by phone administration, is sensitive for detecting MBI in people with MCI. The MBI-C scores indicated that MCI participants had subtle NPS that were correlated to their subjective memory complaints reported by informants, depressive symptoms, and negatively with Instrumental Activities of Daily Living. Further research should be done to clarify the predictive role of NPS in MCI for incident dementia. Show more

Keywords: Behavioral and psychological symptoms of dementia, dementia, mild behavioral impairment, mild cognitive impairment, neuropsychiatric symptoms, preclinical dementia, prodromal dementia

DOI: 10.3233/JAD-180131

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 83-95, 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) has focused 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. 66, no. 1, pp. 97-104, 2018

Authors: Laugisch, Oliver | Johnen, Andreas | Maldonado, Alejandra | Ehmke, Benjamin | Bürgin, Walter | 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 (Aβ1-42 ). 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 Aβ1-42 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. 66, no. 1, pp. 105-114, 2018

Authors: Ehrenberg, Alexander J. | Suemoto, Claudia K. | França Resende, Elisa de Paula | 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. 66, no. 1, pp. 115-126, 2018