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

Authors: Reddy, P. Hemachandra | Swerdlow, Russell H. | Culberson, John | Kang, David | Mitchell, Tedd L. | Smith, Quentin | Suneja, Sanoj | Ory, Marcia G. | Kumar, Subodh | Vijayan, Murali | Morsy, Ahmed | Arandia, Gabriela | Lawrence, J. Josh | George, Elizabeth | Oliver, Darryll | Pradeepkiran, Jangampalli Adi | Yin, Xiangling | Reddy, Arubala P. | Manczak, Maria | Cengiz, Pelin | Karamyan, Vardan T. | Kandimalla, Ramesh | Kuruva, Chandra Sekhar | Willms, Joshua | Ramasubramanian, Bhagavathi | Sawant, Neha | Burugu, Divya | Boles, Annette N. | Lopez, Veronica | Carrasco, Rocio | Aguirre, Cordelia | Thompson, Susan | Blackmon, Joan | Ament, Clay | Wang, Rui | Stephens, Emily R. | Hoang, Brittney | Bass, Kevin | Trippier, Paul C. | Hornback, Christopher | Kottapalli, Pratibha | Kottapalli, Kameswara Rao | Center Biotechnology and Genetics Core Facility | Oddo, Salvatore

Article Type: Abstract

Abstract: The purpose of the ‘First Regional Healthy Aging and Dementia Research Symposium’ was to discuss the latest research in healthy aging and dementia research, public health trends related to neurodegenerative diseases of aging, and community-based programs and research studying health, nutrition, and cognition. This symposium was organized by the Garrison Institute on Aging (GIA) of the Texas Tech University Health Sciences Center (TTUHSC), and was held in Lubbock, Texas, October 24–25, 2018. The Symposium joined experts from educational and research institutions across the United States. The two-day Symposium included all GIA staff and researchers. Students, postdoctoral fellows, and faculty members …involved in dementia research presented at the Symposium. Healthcare professionals, from geriatricians to social workers working with patients with neurodegenerative diseases, also presented. In addition, experts traveled from across the United States to participate. This event was comprised of multiple sessions, each with several oral presentations, followed by questions and answers, and discussion. Show more

DOI: 10.3233/JAD-190252

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2019

Authors: Tan, Rachel H. | Yang, Yue | McCann, Heather | Shepherd, Claire | Halliday, Glenda M.

Article Type: Short Communication

Abstract: The selective loss of von Economo neurons has been linked to the behavioral deficits in behavioral variant frontotemporal dementia (bvFTD) but whether these neurons are affected in bvFTD patients with underlying Alzheimer’s disease (AD) has yet to be established. The present study assesses the von Economo neurons in pathological AD cases clinically diagnosed with either AD or bvFTD. Our results demonstrate no significant loss of von Economo neurons in all pathological AD cases, irrespective of clinical diagnosis or co-existing Lewy body pathology. These results suggest that the behavioral deficits in patients with clinical bvFTD and underlying pathological AD are not …driven by the loss of von Economo neurons. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, Lewy body pathology, Von Economo neurons

DOI: 10.3233/JAD-180900

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Robillard, Julie M. | Wu, Julia M. | Feng, Tanya L. | Tam, Mallorie T.

Article Type: Review Article

Abstract: Background: As the global prevalence of dementia rises, care costs impose a large burden on healthcare systems. Technology solutions in dementia care have the potential to ease this burden. While policies exist to guide and govern the use of dementia care technologies, little is known about how ethical considerations are incorporated into these documents. Objective: The goal of this study was to examine ethics-related content in dementia care technology policies. Methods: We used a two-step data mining approach to collect a sample of dementia technology policies. Policy documents were analyzed using emergent content analysis. Following the …coding of the sample, thematic categories were organized using the principles of biomedical ethics as a framework. Results: A total of 23 policy documents from four Alzheimer associations in four countries were included in our analysis. General ethics considerations and themes related to beneficence were mentioned in 96% of the documents. Thematic categories related to justice were present in 74% of the sample, themes related to non-maleficence appeared in 52% of documents, and themes related to autonomy appeared in 43% of the sample. Conclusion: While ethical considerations are present in existing policies for dementia care technology, these considerations revolve primarily around the benefit of the technologies. Further efforts are needed to provide formal guidance that incorporates both benefits and potential harms. Show more

Keywords: Dementia, ethics, healthcare, technology

DOI: 10.3233/JAD-180938

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Hardcastle, Cheshire | Huang, Hua | Crowley, Sam | Tanner, Jared | Hernaiz, Carlos | Rice, Mark | Parvataneni, Hari | Ding, Mingzhou | Price, Catherine C.

Article Type: Research Article

Abstract: Background: Research shows that older adults can have a decline in three key resting state networks (default mode network, central executive network, and salience network) after total knee arthroplasty and that patients’ pre-surgery brain and cognitive integrity predicts decline. Objectives: First, to assess resting state network connectivity decline from the perspective of nodal connectivity changes in a larger older adult surgery sample. Second, to compare pre-post functional connectivity changes in mild cognitive impairment (MCI) versus non-MCI. Methods: Surgery (n  = 69) and non-surgery (n  = 65) peers completed a comprehensive preoperative neuropsychological evaluation and pre- and acute (within …48 hours) post-surgery/pseudo-surgery functional brain magnetic resonance imaging scan. MCI was classified within both (MCI surgery, n  = 13; MCI non-surgery, n  = 10). Using standard coordinates, we defined default mode network, salience network, central executive network, and the visual network (serving as a control network). The functional connectivity of these networks and brain areas (nodes) that make up these networks were examined for pre-post-surgery changes through paired samples t -test and ANOVA. Results: There was a decline in RSN connectivity after surgery (p  < 0.05) only in the three cognitive networks (not the visual network). The default mode and salience network showed nodal connectivity changes (p  < 0.01). MCI surgery had greater functional connectivity decline in DMN and SN. Non-surgery participants showed no significant functional connectivity change. Conclusion: Surgery with general anesthesia selectively alters functional connectivity in major cognitive resting state networks particularly in DMN and SN. Participants with MCI appear more vulnerable to these functional changes. Show more

Keywords: Anesthesia, cognitive dysfunction, dementia, functional magnetic resonance imaging, mild cognitive impairment, orthopedics, surgery

DOI: 10.3233/JAD-180932

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Åhman, Hanna Bozkurt | Giedraitis, Vilmantas | Cedervall, Ylva | Lennhed, Björn | Berglund, Lars | McKee, Kevin | Kilander, Lena | Rosendahl, Erik | Ingelsson, Martin | Åberg, Anna Cristina

Article Type: Research Article

Abstract: Background: Tools to identify individuals at preclinical stages of dementia disorders are needed to enable early interventions. Alterations in dual-task performance have been detected early in progressive neurodegenerative disorders. Hence, dual-task testing may have the potential to screen for cognitive impairment caused by neurodegeneration. Exploring correlations between dual-task performance and biomarkers of neurodegeneration is therefore of interest. Objective: To investigate correlations between Timed Up-and-Go dual-task (TUGdt) outcomes and Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 42 (Aβ42 ), total tau (t-tau), and phosphorylated tau (p-tau). Methods: This cross-sectional cohort study included 90 participants (age range …49–84 years) undergoing memory assessment, who were subsequently diagnosed with AD, other dementia disorders, mild cognitive impairment, or subjective cognitive impairment. TUG combined with “Naming Animals” (TUGdt NA) and “Months Backwards” (TUGdt MB), respectively, were used to assess dual-task performance. The number of correct words and time taken to complete the tests were measured. The CSF biomarkers were analysed by ELISA. Spearman’s rank correlation was used for analyses between TUGdt outcomes (TUGdt NA and TUGdt MB), and CSF biomarkers, adjusted for age, gender, and educational level. Results: The number of correct words, as well as the number of correct words/10 s during TUGdt NA correlated negatively to CSF t-tau and p-tau. No correlations were found between any time scores and CSF biomarkers. Conclusion: The correlations between TUGdt NA and t-tau and p-tau may indicate that neurodegeneration affects dual-task performance. Longitudinal studies are needed to further explore dual-task testing in screening for cognitive impairment due to neurodegeneration. Show more

Keywords: Alzheimer’s disease, attention, biomarkers, cerebrospinal fluid, dementia, executive function, gait, mild cognitive impairment, subjective cognitive impairment

DOI: 10.3233/JAD-181265

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Elsworthy, Richard J. | Aldred, Sarah

Article Type: Review Article

Abstract:  Depression is a common co-morbidity seen in people with Alzheimer’s disease (AD). However, the successful treatment of depressive symptoms in people with AD is rarely seen. In fact, multiple randomized controlled trials have shown selective serotonin reuptake inhibitors (SSRIs), the current best recommended treatment for depression, to be ineffective in treating depressive symptoms in people with AD. One explanation for this lack of treatment effect may be that depressive symptoms can reflect the progression of AD, rather than clinical depression and are a consequence of more severe neurodegeneration. This raises several questions regarding not only the efficacy of SSRIs in …the treatment of depression in people with AD but also regarding the accuracy of diagnosis of depression in AD. However, there may be a rationale for the prescription of SSRIs in early AD. Even in the absence of depression, SSRIs have been shown to slow the conversion from mild cognitive impairment to AD. This may be attributed to the effect of SSRIs on the processing of amyloid-β precursor protein, which may cause a reduction in the accumulation of amyloid-β. Thus, although SSRIs may lack efficacy in treating depression in people with AD, they may hold therapeutic potential for treating and delaying the progression of AD especially if treatment begins in the early stages of AD. This article reviews the current consensus for SSRI treatment of depression in people with AD and highlights the possibility of SSRIs being a treatment option for delaying the progression of AD. Show more

Keywords: Aging, Alzheimer’s disease, amyloidosis, depression, second generation antidepressive agents

DOI: 10.3233/JAD-180780

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Bunai, Tomoyasu | Kakimoto, Akihiro | Yoshikawa, Etsuji | Terada, Tatsuhiro | Ouchi, Yasuomi

Article Type: Research Article

Abstract: Background: Amyloid imaging with positron emission tomography (PET) often comes with glucose metabolic imaging in diagnosis of Alzheimer’s disease (AD). Objective: The present purpose was to explore the clinical valence of early amyloid-β (Aβ) PET scans to determine whether they could substitute for other imaging biomarkers (early and delayed Aβ images of 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) images) in the AD spectrum. Methods: Thirty healthy control subjects, 20 patients with mild cognitive impairment, and 45 patients with AD underwent 11 C-PIB and 18 F- FDG PET. Image analyses were performed with three-dimensional …stereotactic surface projection and Brodmann’s area regions-of-interest methods. Since early accumulation of PIB (ePIB) reflects blood flow, we classified all subjects according to the level of ePIB in the posterior cingulate gyrus, precuneus, and lateral parietal cortex. We compared the PET parameters (ePIB, delayed-phase PIB accumulation or dPIB, FDG) to determine whether ePIB-based categorization reflected Aβ deposition in a Braak stage-related fashion. Results: We found that ePIB images were similar to 18 F-FDG images and that the progress of Aβ deposition deduced from the reduction in ePIB index was similar to the pathological progress of Braak staging. A decrease in the ePIB level in the posterior cingulate gyrus, precuneus, and parietal cortex was shown to correspond to greater and wider Aβ deposition in the medial frontal, anterior, and posterior cingulate gyri. Conclusions: The early-phase 11 C-PIB index can be an alternative to the neurogenerative markers of glucose hypometabolism and reflects the Braak stage of Aβ deposition in the living AD brain. Show more

Keywords: Alzheimer’s disease, amyloid, Braak stage, 11C-PIB, 18F-FDG, glucose, positron emission tomography

DOI: 10.3233/JAD-181188

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Nation, Daniel A. | Ho, Jean K. | Dutt, Shubir | Han, S. Duke | Lai, Mark H.C. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: A clinical diagnosis of cognitive impairment is traditionally based on a single cognitive exam, but serial cognitive testing can be sensitive to subtle cognitive changes in asymptomatic individuals and inform cognitive trajectory. Objective: We evaluated the prognostic utility of identifying longitudinal neuropsychological decline along with single cognitive exam and Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers in predicting dementia. We also examined brain volumetric differences based on decline trajectories. Method: Regression models quantified 12-month neuropsychological decline relative to normative expectations among non-demented older adults (N  = 1,074). Progression to dementia over follow-up (18-120 months) was diagnosed …using independent modes of assessment. Results: In Cox regression models controlling for age, sex, education, apolipoprotein E4, and baseline cognitive diagnosis, neuropsychological decline predicted increased dementia risk, χ 2  = 69.861, p  < 0.001, odds ratio = 2.841, even after correction for CSF biomarkers (amyloid-β , phosphorylated tau, total tau), χ 2  = 26.365, p  < 0.001, odds ratio = 2.283. Voxel-based morphometry analysis indicated smaller hippocampal and medial temporal volume in participants with neuropsychological decline. Conclusions: Longitudinal diagnosis of neuropsychological decline improved prognostic accuracy beyond single cognitive exam diagnoses and AD CSF biomarkers, even in asymptomatic older adults. Older adults with a trajectory of neuropsychological decline exhibit smaller medial temporal and hippocampal brain volume. Longitudinal diagnostic approaches may benefit selection and randomization procedures for AD clinical trials in asymptomatic individuals. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, dementia

DOI: 10.3233/JAD-180525

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Kwon, Sunkuk | Moreno-Gonzalez, Ines | Taylor-Presse, Kathleen | Edwards III, George | Gamez, Nazaret | Calderon, Olivia | Zhu, Banghe | Velasquez, Fred Christian | Soto, Claudio | Sevick-Muraca, Eva M.

Article Type: Research Article

Abstract:  Cerebrospinal fluid (CSF) outflow from the brain occurs through absorption into the arachnoid villi and, more predominantly, through meningeal and olfactory lymphatics that ultimately drain into the peripheral lymphatics. Impaired CSF outflow has been postulated as a contributing mechanism in Alzheimer’s disease (AD). Herein we conducted near-infrared fluorescence imaging of CSF outflow into the peripheral lymph nodes (LNs) and of peripheral lymphatic function in a transgenic mouse model of AD (5XFAD) and wild-type (WT) littermates. CSF outflow was assessed from change in fluorescence intensity in the submandibular LNs as a function of time following bolus, an intrathecal injection of indocyanine …green (ICG). Peripheral lymphatic function was measured by assessing lymphangion contractile function in lymphatics draining into the popliteal LN following intradermal ICG injection in the dorsal aspect of the hind paw. The results show 1) significantly impaired CSF outflow into the submandibular LNs of 5XFAD mice and 2) reduced contractile frequency in the peripheral lymphatics as compared to WT mice. Impaired CSF clearance was also evidenced by reduction of fluorescence on ventral surfaces of extracted brains of 5XFAD mice at euthanasia. These results support the hypothesis that lymphatic congestion caused by reduced peripheral lymphatic function could limit CSF outflow and may contribute to the cause and/or progression of AD. Show more

Keywords: Cerebrospinal fluid outflow, fluorescence imaging, intrathecal, lymphatic system

DOI: 10.3233/JAD-190013

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Koulousakis, Philippos | Andrade, Pablo | Visser-Vandewalle, Veerle | Sesia, Thibaut

Article Type: Review Article

Abstract: The nucleus basalis of Meynert (nbM) was first described at the end of the 19th century and named after its discoverer, Theodor Meynert. The nbM contains a large population of cholinergic neurons that project their axons to the entire cortical mantle, the olfactory tubercle, and the amygdala. It has been functionally associated with the control of attention and maintenance of arousal, both key functions for appropriate learning and memory formation. This structure is well-conserved across vertebrates, although its degree of organization varies between species. Since early in the investigation of its functional and pathological significance, its degeneration has been linked …to various major neuropsychiatric disorders. For instance, Lewy bodies, a hallmark in the diagnosis of Parkinson’s disease, were originally described in the nbM. Since then, its involvement in other Lewy body and dementia-related disorders has been recognized. In the context of recent positive outcomes following nbM deep brain stimulation in subjects with dementia-associated disorders, we review the literature from an historical perspective focusing on how the nbM came into focus as a promising therapeutic option for patients with Alzheimer’s disease. Moreover, we will discuss what is needed to further develop and widely implement this approach as well as examine novel medical indications for which nbM deep brain stimulation may prove beneficial. Show more

Keywords: Acetylcholine, Alzheimer’s disease, deep brain stimulation, nucleus basalis of Meynert

DOI: 10.3233/JAD-180133

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019