Journal of Alzheimer's Disease - Volume 66, issue 4

Authors: Smedinga, Marthe | Tromp, Krista | Schermer, Maartje H.N. | Richard, Edo

Article Type: Review Article

Abstract: Background: The shift to defining Alzheimer’s disease (AD) as a biological continuum, which is characterized by the presence of biomarkers instead of clinical symptoms, has sparked a widespread debate. Insight into the given arguments and their underlying moral values is crucial to ensure well-considered and appropriate AD biomarker testing in the future. Objective: To critically review the arguments in favor of or against AD biomarker testing in people with no or mild cognitive impairment and to explicate their underlying moral values. Methods: Seven databases were systematically searched for publications mentioning arguments of interest. Arguments are identified …using qualitative data-analysis and evaluated within an ethical framework. Results: Our search yielded 3,657 articles of which 34 met the inclusion criteria. We discuss the clusters of arguments separate from their evaluation and the assessment of the debate as a whole. The right to know, which derives from the moral value of respect for autonomy, is a central argument in favor of biomarker testing. On the other hand, fear of the disease and lack of a disease-modifying treatment may result in a negative balance of good over inflicted harms, which argues against its use. Conclusion: Critical evaluation and weighing of the given arguments in a specific context, within an ethical framework, demonstrates the necessity to differentiate between what we hope or expect from research and where we currently stand. While AD biomarkers may have an indispensable value for research, the current advantage for clinical practice appears limited. Show more

Keywords: Alzheimer’s disease, bioethical issues, biomarkers, disclosure, early diagnosis, ethics

DOI: 10.3233/JAD-180638

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1309-1322, 2018

Authors: Jiang, Haowei | Jayadev, Suman | Lardelli, Michael | Newman, Morgan

Article Type: Review Article

Abstract: PRESENILIN 1 (PSEN1 ) and PRESENILIN 2 (PSEN2 ) genes are loci for mutations causing familial Alzheimer’s disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2 . As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, …indicating that PSEN2 plays a particular role in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, γ-secretase, PRESENILIN 1, PRESENILIN 2

DOI: 10.3233/JAD-180656

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1323-1339, 2018

Authors: Menardi, Arianna | Pascual-Leone, Alvaro | Fried, Peter J. | Santarnecchi, Emiliano

Article Type: Review Article

Abstract: Comforts in modern society have generally been associated with longer survival rates, enabling individuals to reach advanced age as never before in history. With the increase in longevity, however, the incidence of neurodegenerative diseases, especially Alzheimer’s disease, has also doubled. Nevertheless, most of the observed variance, in terms of time of clinical diagnosis and progression, often remains striking. Only recently, differences in the social, educational and occupational background of the individual, as proxies of cognitive reserve (CR), have been hypothesized to play a role in accounting for such discrepancies. CR is a well-established concept in literature; lots of studies have …been conducted in trying to better understand its underlying neural substrates and associated biomarkers, resulting in an incredible amount of data being produced. Here, we aimed to summarize recent relevant published work addressing the issue, gathering evidence for the existence of a common path across research efforts that might ease future investigations by providing a general perspective on the actual state of the arts. An innovative model is hereby proposed, addressing the role of CR across structural and functional evidences, as well as the potential implementation of non-invasive brain stimulation techniques in the causal validation of such theoretical frame. Show more

Keywords: Aging, Alzheimer’s disease, cognitive reserve, diffusion tensor imaging, electroencephalography, functional magnetic resonance imaging, magnetic resonance imaging, positron emission tomography, transcranial magnetic stimulation

DOI: 10.3233/JAD-180549

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1341-1362, 2018

Authors: Eikelboom, Willem S. | van Rooij, Jeroen G. J. | van den Berg, Esther | Coesmans, Michiel | Jiskoot, Lize C. | Singleton, Ellen | Ossenkoppele, Rik | van Swieten, John C. | Seelaar, Harro | Papma, Janne M.

Article Type: Short Communication

Abstract: Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer’s disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the underrecognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.

Keywords: Alzheimer’s disease, behavior, dementia, diagnosis, neuropsychiatry

DOI: 10.3233/JAD-180700

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1363-1369, 2018

Authors: Gant, John C. | Kadish, Inga | Chen, Kuey-Chu | Thibault, Olivier | Blalock, Eric M. | Porter, Nada M. | Landfield, Philip W.

Article Type: Short Communication

Abstract: Aging is the leading risk factor for idiopathic Alzheimer’s disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2 + dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate. Considering that humans recapitulate many aspects of animal brain aging, these results support the hypothesis that aging-related Ca2 + dysregulation occurs in human entorhinal …neurons and promotes NFT pathogenesis. Show more

Keywords: Afterhyperpolarization, aging models, calcium-dependent, cytoskeleton, FKBP, hippocampus, neurofibrillary progression, ryanodine receptor

DOI: 10.3233/JAD-180618

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1371-1378, 2018

Authors: Okuya, Makoto | Matsunaga, Shinji | Ikuta, Toshikazu | Kishi, Taro | Iwata, Nakao

Article Type: Short Communication

Abstract: A systematic review and meta-analysis of the efficacy/safety of intravenous immunoglobulin (IVIG) administration in mild-to-moderate Alzheimer’s disease (AD) patients was performed. Six randomized double-blind, placebo-controlled trials (n  = 801) were included in this study. No significant difference in cognitive function was observed between the groups. Moreover, IVIG was inferior to placebo in behavioral disturbances (mean difference = 2.19). Further, IVIG administration was associated with a higher incidence of rash than placebo. Our results do not support IVIG administration for mild-to-moderate AD, suggesting that IVIG is not effective to treat mild-to-moderate AD and that it deteriorates behavioral and psychological symptoms of dementia in mild-to-moderate …AD. Show more

Keywords: Efficacy, intravenous immunoglobulin, meta-analysis, mild-to-moderate Alzheimer’s disease, safety, systematic review

DOI: 10.3233/JAD-180888

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1379-1387, 2018

Authors: Lombardi, Gemma | Polito, Cristina | Berti, Valentina | Bagnoli, Silvia | Nacmias, Benedetta | Pupi, Alberto | Sorbi, Sandro

Article Type: Short Communication

Abstract: Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE ɛ 4/ɛ 4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer’s disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors.

Keywords: Alzheimer’s disease, bilingualism, cognitive reserve, obstructive sleep apnea, prevention

DOI: 10.3233/JAD-180736

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1389-1395, 2018

Authors: Llorente, Patricia | Kristen, Henrike | Sastre, Isabel | Toledano-Zaragoza, Ana | Aldudo, Jesús | Recuero, María | Bullido, María J.

Article Type: Research Article

Abstract: Amyloid-β (Aβ), a major component of senile plaques, is generated via the proteolysis of amyloid-β protein precursor (AβPP). This cleavage also produces AβPP fragment-derived oligomers which can be highly neurotoxic. AβPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer’s disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AβPP proteolysis (β-secretase activity) and Aβ clearance (Aβ degradative activity). The present work examines the effect …of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AβPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AβPP and secreted α -secretase-cleaved soluble AβPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS. Show more

Keywords: amyloid-β , amyloid-β protein precursor, cathepsin B, free radicals, oligomer, oxidative stress

DOI: 10.3233/JAD-170159

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1397-1408, 2018

Authors: Brashear, H. Robert | Ketter, Nzeera | Bogert, Jennifer | Di, Jianing | Salloway, Stephen P. | Sperling, Reisa

Article Type: Research Article

Abstract: Background: Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer’s disease in bapineuzumab phase III studies. Objectives: Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function. Methods: A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ 4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists. Results: Treatment-emergent ARIA-E occurred in 15.8% of bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ɛ 4 noncarriers, the percentage of …patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals. Conclusions: Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function. Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302) Show more

Keywords: Amyloid-related imaging abnormality, bapineuzumab, clinical evaluation

DOI: 10.3233/JAD-180675

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1409-1424, 2018

Authors: Bartolotti, Nancy | Disouky, Ahmed | Kalinski, Arthur | Elmann, Anat | Lazarov, Orly

Article Type: Research Article

Abstract: Plant derivatives offer a novel and natural source of therapeutics. The desert plant Achillea fragrantissima (Forssk) Sch. Bip (Af) is characterized by protective antioxidative and anti-inflammatory properties. Here, we examined the effect of two Af -derived phytochemicals on learning and memory, amyloid-β protein precursor (AβPP) metabolism, and tau phosphorylation in the familial Alzheimer’s disease-linked APPswe/PS1Δ E9 mouse model. We observed that mice that were injected with the phytochemicals showed a trend of improvement, albeit statistically insignificant, in the Novel Object Recognition task. However, we did not observe improvement in contextual fear conditioning, suggesting that the benefits of treatment …may be either indirect or task-specific. In addition, we observed an increase in the full-length form of AβPP in the brains of mice treated with Af –derived phytochemicals. Interestingly, both in vivo and in vitro , there was no change in levels of soluble Aβ, oligomeric Aβ, or the carboxyl terminus fragments of AβPP (APP-CTFs), suggesting that the increase in full length AβPP does not exacerbate AβPP pathology, but may stabilize the full-length form of the molecule. Together, our data suggest that phytochemicals present in Af may have a modest positive impact on the progression of Alzheimer’s disease. Show more

Keywords: Achillolide A, Alzheimer’s disease, amyloid-β protein precursor, flavonoids, sesquiterpene lactones, 3, 5, 4’-trihydroxy-6, 7, 3’-trimethoxyflavone

DOI: 10.3233/JAD-180068

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1425-1435, 2018