Journal of Alzheimer's Disease - Volume 68, issue 4

Authors: Watt, Andrew D. | Jenkins, Nicole L. | McColl, Gawain | Collins, Steven | Desmond, Patricia M.

Article Type: Review Article

Abstract: There is hope that the continuing efforts of researchers will yield a disease-modifying drug for Alzheimer’s disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer’s disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such …a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients’ rights and well-being are protected when such therapeutic options become available. Show more

Keywords: Alzheimer’s disease, ethics, late-stage, restoration, palliative care, therapeutics

DOI: 10.3233/JAD-180865

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1311-1316, 2019

Authors: Rosen, Allyson C. | Toy, Leslie | Langston, Ashley H.

Article Type: Research Article

Abstract: The potential for successful disease modifying treatments for Alzheimer’s disease (AD) opens up the possibility that there will be a large cohort of patients living with late-stage dementia and poor quality of life. There must thus be a parallel effort to leverage restorative therapies that improve quality of life in these patients. With the potential for stopping the onset of AD in new patients must come a commitment to those patients living with this chronic disability for many more years than first thought. Legal and ethical implications surrounding who makes decisions and equity in receiving care will become increasingly important …if AD is no longer a terminal illness. Show more

Keywords: Alzheimer’s disease, dementia, end of life, hospice, neuroethics, therapy, quality of life

DOI: 10.3233/JAD-181193

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1317-1319, 2019

Authors: Watt, Andrew D. | Jenkins, Nicole L. | McColl, Gawain | Collins, Steven | Desmond, Patricia M.

Article Type: Research Article

Abstract: Rosen et al. thoughtfully extend the ethical discussion surrounding disease-modifying therapies in late-stage Alzheimer’s disease (AD) to correctly emphasize that the perceived quality of life (QoL) of the individual living with the disease is a critical component to decisions regarding their clinical care. The primary purpose of our original article regarding the use of disease-modifying therapeutics in late-stage AD was to ensure that those affected by AD and their primary care team are empowered to make informed care decisions in the best interest of the individual living with AD. Consequently, it appears axiomatic that major therapeutic decisions need to incorporate …consideration of the current and future QoL of individuals living with dementia; however, in the absence of effective restorative therapies, it is important to acknowledge the context within which extant QoL measures were developed and question whether such measures are adequate to inform treatment decisions that may hold the potential to significantly or perhaps indefinitely prolong severe disability. Show more

Keywords: Alzheimer’s disease, ethics, late-stage, restoration, quality of life, therapeutics

DOI: 10.3233/JAD-190033

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1321-1323, 2019

Authors: Wuttke-Linnemann, Alexandra | Baake, Ricarda | Fellgiebel, Andreas

Article Type: Review Article

Abstract: Patients with dementia (PWD) and their caregivers experience long-term stress, leading to accelerated disease progression and to stress-related morbidity. Previous research focused on intrapersonal biopsychological stress responses. Quite recently, dyadic interrelations between caregivers and PWD and their effects on stress and caregiver burden have received more attention, giving rise to dyadic intervention studies. However, while it is of importance to consider both the patient and the caregiver from a dyadic point of view, evaluation of these dyadic interventions considering underlying mechanisms is still lacking. We therefore extend the current literature on dyadic processes between PWD and caregivers by transferring the …knowledge about underlying stress-modulating dyadic processes in healthy couples to the dementia patient-caregiver constellation. By targeting dyadic stress co-regulation between PWD and caregivers, we expect significant therapeutic effectiveness. The aims of this article are two-fold: 1) We aim to provide a rationale for incremental benefits of considering dyadic processes among caregivers and PWD by means of elucidating underlying mechanisms and 2) we aim to emphasize the need to evaluate these underlying mechanisms by means of objective physiological stress markers in both PWD and caregivers. Knowledge on these underlying mechanisms will ultimately help developing dyadic interventions tailored to the needs of both PWD and their caregivers. Show more

Keywords: Cortisol, dementia care management, hypothalamic-pituitary-adrenal axis, stress physiology, systemic approach

DOI: 10.3233/JAD-181025

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1325-1337, 2019

Authors: Wadhawan, Abhishek | Stiller, John W. | Potocki, Eileen | Okusaga, Olaoluwa | Dagdag, Aline | Lowry, Christopher A. | Benros, Michael E. | Postolache, Teodor T.

Article Type: Review Article

Abstract: Given the increasing rate of death by suicide in the United States, it is imperative to examine specific risk factors and to identify possible etiologies of suicidal behavior in at-risk clinical subpopulations. There is accumulating evidence to support an elevated risk of death by suicide in individuals with a history of traumatic brain injury (TBI). In this review article, after defining terms used in suicidology, we discuss the associations of TBI with death by suicide, suicide attempt, and suicidal ideation. A model for repetitive TBIs, leading to chronic traumatic encephalopathy, is also discussed as a neuroinflammatory process, with discussion about …its possible link with suicide. The review concludes with an overview of interventions to prevent suicidal behavior. Show more

Keywords: Chronic traumatic encephalopathy, death by suicide, inflammation, neuroinflammation, suicidal behavior, traumatic brain injury

DOI: 10.3233/JAD-181055

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1339-1370, 2019

Authors: Manigrasso, Maurizio | Protano, Carmela | Vitali, Matteo | Avino, Pasquale

Article Type: Review Article

Abstract: This paper presents an overview of the literature studies on the sources of ultrafine particles (UFPs), nanomaterials (NMs), and nanoparticles (NPs) occurring in indoor (occupational and residential) and outdoor environments. Information on the relevant emission factors, particle concentrations, size, and compositions is provided, and health relevance of UFPs and NPs is discussed. Particular attention is focused on the fraction of particles that upon inhalation deposit on the olfactory bulb, because these particles can possibly translocate to brain and their possible role in neurodegenerative diseases is an important issue emerging in the recent literature.

Keywords: Health relevance, indoor, nanomaterials, neurodegenerative diseases, outdoor, ultrafine particles

DOI: 10.3233/JAD-181266

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1371-1390, 2019

Authors: Guo, Huifang | Zhao, Zhaohua | Zhang, Ruisan | Chen, Peng | Zhang, Xiaohua | Cheng, Fan | Gou, Xingchun

Article Type: Review Article

Abstract: Aging societies have high incidence rates of Alzheimer’s disease (AD). AD is diagnosed at later disease stages and has a poor prognosis, and effective drugs and treatments for AD are lacking. The molecular mechanism of AD is not clear, and current research focuses primarily on amyloid-β (Aβ) deposition and tau protein hyperphosphorylation. Aβ deposition is the most frequently hypothesized initiating factor of AD, and Aβ clearance during the pathogenesis of AD may be an optional strategy to suppress AD development. Monocytes play important roles in the peripheral clearance of Aβ. Therefore, the present review summarizes our current knowledge of the …potential roles of infiltrating macrophages, circulating monocytes, and Kupffer cells in the peripheral clearance of Aβ in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, infiltrating macrophages, Kupffer cells, monocytes, peripheral clearance

DOI: 10.3233/JAD-181177

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1391-1400, 2019

Authors: Bianchetti, Angelo | Ferrara, Nicola | Padovani, Alessandro | Scarpini, Elio | Trabucchi, Marco | Maggi, Stefania

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) generally evolves in a gradually progressive decline in memory and non-memory cognitive domains that may eventually decay to dementia. This process might be preventable by improving early detection of the MCI syndrome followed by proper and timely interventions. The aim of this work was providing helpful indications for a standardized early diagnosis of MCI, mainly focusing on the Italian elderly population. We reviewed here MCI epidemiology and classification, as well as the most recent advancements in early detection of the patient with MCI in the Italian scenario. Specialist centers in connection with general practitioners (GPs) have …been established across the country and designated as Centers for Cognitive Disorders and Dementia (CDCD). CDCDs are dedicated to the diagnosis and management of patients for all forms of dementia across all the complex staging spectrum. New tools were made available by the advancements of imaging techniques and of the research on biomarkers, leading to novel approaches based on the combination of imaging and biomarker detection, to improve accuracy and effectiveness in the early diagnosis of MCI. Moreover, patient genotyping, alone or in combination with other techniques, was also revealed as a promising method in evaluating and preventing MCI progression. We recommend the introduction of all these novel tools in the diagnostic practice of the specialist centers and that further efforts and resources are spent into the research of the most effective techniques and biomarkers to be introduced as first-level tests into the practice of early diagnosis of MCI. Show more

Keywords: Biomarkers, early diagnosis, genotyping, imaging, mild cognitive impairment, neuropsychological assessment

DOI: 10.3233/JAD-181253

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1401-1414, 2019

Authors: Kuhla, Angela | Brichmann, Elaine | Rühlmann, Claire | Thiele, Robin | Meuth, Lou | Vollmar, Brigitte

Article Type: Research Article

Abstract: Epidemiological studies suggest that individuals with diabetes mellitus are at greater risk of developing Alzheimer’s disease. A well-known insulin-sensitizing drug and the most widely prescribed oral medication for diabetes is metformin. There is evidence that metformin acts in a neuroprotective manner via the AMPK/mTOR pathway by inhibiting the tau phosphorylation. In addition, it is known that metformin upregulates Fgf21, which in turn activates the AMPK/mTOR pathway and mediates neuroprotection. Thus, metformin-induced Fgf21 release may be involved in AMPK/mTOR activation. However, some studies reported that metformin causes cognition impairment. Due to the controversial data on the neuroprotective properties of metformin, we …treated Apolipoprotein E deficient (ApoE – /–) mice, a mouse model of tauopathy, with metformin for 18 weeks. Metformin-treated mice revealed increased expression of lipogenic genes, i.e., lxr α and srebp1c . In line with this, metformin caused an increase in plasma triglyceride leading to enhanced gliosis as indicated by an increase of GFAP-positive cells. Although the systemic Fgf21 concentration was increased, metformin did not activate the FgfR1c/AMPK/mTOR pathway suggesting a Fgf21-resistant state. Further, metformin-treated mice showed increased tau phosphorylation and reduced numbers of NeuN-and PSD95-positive cells. Thus, metformin-associated lipogenesis as well as inflammation aggravated neurodegenerative processes in ApoE – /– mice. Consequently, this study supports previous observations showing that metformin causes impairment of cognition. Show more

Keywords: Alzheimer’s disease, ApoE deficiency, Fgf21, metformin, mTOR, neuro-inflammation, pAMPK, tau phosphorylation

DOI: 10.3233/JAD-181017

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1415-1427, 2019

Authors: Wright, Lauren M. | Stein, Thor D. | Jun, Gyungah | Chung, Jaeyoon | McConnell, Kate | Fiorello, Marissa | Siegel, Nicole | Ness, Steven | Xia, Weiming | Turner, Kelley L. | Subramanian, Manju L.

Article Type: Research Article

Abstract: Background: The eye may serve as source for diagnostic testing for early detection of Alzheimer’s disease (AD). Examination of amyloid-β (Aβ) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods. Objective: To evaluate levels of Aβ and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD. Methods: A prospective, single-center, multi-surgeon cohort study. Vitreous humor samples from 80 eyes were measured quantitatively for Aβ40-42 , pTau, and tTau. Linear regression was used to test associations …between AD biomarker levels, Mini-Mental State Exam (MMSE), and serum apolipoprotein E (APOE) allele status, with adjustment for age, sex, and education level of patients. Results: Lower MMSE scores were significantly associated with lower levels of vitreous Aβ40 (p  = 0.015), Aβ42 (p  = 0.0066), and tTau (p  = 0.0085), and these biomarkers were not associated with any pre-existing eye conditions. Presence of the ɛ 4 allele and the ɛ 2 allele approached significance with reduced Aβ40 level (p  = 0.053) and increased p-Tau level (p  = 0.056), respectively. Conclusion: Patients with poor cognitive function have significantly lower vitreous humor levels of AD-related biomarkers Aβ40 , Aβ42 , and tTau. These biomarkers do not correlate with underlying eye conditions, suggesting their specificity in association with cognitive change. This is the first study to our knowledge to correlate cognition with AD-related proteins in the vitreous humor. Results suggest ocular proteins may have a role for early dementia detection in individuals at risk for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, Mini-Mental State Exam, ocular biomarkers, tau, vitreous

DOI: 10.3233/JAD-181104

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1429-1438, 2019