Journal of Alzheimer's Disease - Volume 75, issue 2

Authors: Vijayan, Murali | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: This article reviews recent advances in the study of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and their functions in type 2 diabetes mellitus (T2DM), ischemic stroke (IS), and vascular dementia (VaD). miRNAs and lncRNAs are gene regulation markers that both regulate translational aspects of a wide range of proteins and biological processes in healthy and disease states. Recent studies from our laboratory and others have revealed that miRNAs and lncRNAs expressed differently are potential therapeutic targets for neurological diseases, especially T2DM, IS, VaD, and Alzheimer’s disease (AD). Currently, the effect of aging in T2DM, IS, and VaD and the cellular …and molecular pathways are largely unknown. In this article, we highlight results from the works on the molecular connections between T2DM and IS, and IS and VaD. In each disease, we also summarize the pathophysiology and the differential expressions of miRNAs and lncRNAs. Based on current research findings, we hypothesize that 1) T2DM bi-directionally and age-dependently induces IS and VaD, and 2) these changes are precursors to the onset of dementia in elderly people. Research into these hypotheses is required to examine further whether research efforts on reducing T2DM, IS, and VaD may affect dementia and/or delay the AD disease process in the aged population. Show more

Keywords: Aging, Alzheimer’s disease, cross-talk, interaction, ischemic stroke, long noncoding RNAs, microRNAs, type 2 diabetes mellitus, vascular dementia

DOI: 10.3233/JAD-200070

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 353-383, 2020

Authors: Liu, Bo | Liu, Jie | Shi, Jing-Shan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a highly age-related cognitive decline frequently attacking the elderly. Senescence-accelerated mouse-prone 8 (SAMP8) is an ideal model to study AD, displaying age-related learning and memory disorders. SAMP8 mice exhibit most features of pathogenesis of AD, including an abnormal expression of anti-aging factors, oxidative stress, inflammation, amyloid-β (Aβ) deposits, tau hyperphosphorylation, endoplasmic reticulum stress, abnormal autophagy activity, and disruption of intestinal flora. SAMP8 mice, therefore, have visualized the understanding of AD, and also provided effective ways to find new therapeutic targets. This review focused on the age-related pathogenesis in SAMP8 mice, to advance the understanding of age-related …learning and memory decline and clarify the mechanisms. Furthermore, this review will provide extensive foundations for SAMP8 mice used in therapeutics for AD. Show more

Keywords: Abnormal autophagy activity, age-related pathogenesis, amyloid-β deposits, anti-aging factors, disruption of intestinal flora, endoplasmic reticulum stress, inflammation, oxidative stress, senescence-accelerated mouse-prone 8, tau hyperphosphorylation

DOI: 10.3233/JAD-200063

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 385-395, 2020

Authors: Mandal, Pravat K. | Shukla, Deepika

Article Type: Editorial

Abstract: Magnetic resonance spectroscopy (MRS) plays a substantial role in the non-invasive detection of brain neurochemicals, antioxidants, and neurotransmitters. Quantitative monitoring of these neurochemicals and neurotransmitters in the brain has a profound application for the understanding of brain disorders. Significant progress in the MR scanner as well as MR pulse sequence development to detect in vivo neurochemicals has been accomplished. The processing of MR signal from these low abundant neurochemicals/neurotransmitters should be very robust and sensitive in order to provide distinctive observations of disease-related neurochemical alterations and their absolute quantitation to aid in early clinical diagnosis. We highlight the diversity …in currently available MRS processing tools, and recently introduced, KALPANA, a promising package integrating the end-to-end processing as well as robust quantitation of neurochemicals in a user-friendly approach through a graphical user interface. This further necessitates the futuristic need for advanced MRS processing pipeline and the respective readout that can help in early diagnosis and prognosis of diseases in the clinical environment. Show more

Keywords: Absolute quantitation, clinical study, KALPANA, magnetic resonance spectroscopy, signal processing

DOI: 10.3233/JAD-191351

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 397-402, 2020

Authors: Malhotra, Chetna | Vishwanath, Padmini | Yong, Jing Rong | Østbye, Truls | Seow, Dennis | Yap, Phillip | Tan, Lay Ling | Tham, Weng Yew | Vaingankar, Janhavi | Foo, Jason | Tan, Boon Yeow | Tong, Kamun | Ng, Wai Chong | Allen Jr, John Carson | Malhotra, Rahul | Tan, Weng Mooi | Wee, Shiou Liang | Ng, Li Ling | Goveas, Richard | Mok, Vanessa | Sim, Alisson | Ng, Wei Fern | Wong, Hon Khuan | Balasundaram, Bharathi | Tan, Rui Qi | Ong, Pui Sim | Cheong, Chin Yee | Yee Chung Pheng, Alethea | Tiong, Christina | Hum, Allyn | Lee, Angel | Finkelstein, Eric A.

Article Type: Research Article

Abstract: Although many persons with severe dementia (PWSDs) are cared for at home by their family caregivers, few studies have assessed end of life (EOL) care experiences of PWSDs. We present the protocol for the PISCES study (Panel study Investigating Status of Cognitively impaired Elderly in Singapore) which aims to describe the clinical course, health care utilization, and expenditures for community-dwelling PWSDs; and perceived burden, coping, resilience, anticipatory and prolonged grief among their caregivers. This ongoing multi-center prospective longitudinal study is recruiting primary informal caregivers of 250 PWSDs from major restructured public hospitals, community hospitals, home care foundations, and hospices in …Singapore. Caregivers are surveyed every four months for two years or until the PWSD passes away and then at eight weeks and six months post-death to assess the bereavement of the caregiver. Survey questionnaires included validated tools to assess PWSDs’ quality of life, suffering, behaviors, functional status, resource utilization; and caregiver’s satisfaction with care, awareness of prognosis, care preferences, resilience, coping, perceived burden, distress, positive aspects of caregiving, anticipatory grief, and bereavement adjustment. We also conduct qualitative in-depth interviews with a sub-sample of caregivers. The survey data is being linked with medical and billing records of PWSDs. The study has been approved by an ethics board. Results from the study will be disseminated through publications and presentations targeting researchers, policy makers and clinicians interested in understanding and improving EOL care for PWSDs and their caregivers. Show more

Keywords: Dementia, end of life, health care utilization, palliative care, Singapore, http://www.clinicaltrials.gov (NCT03382223)

DOI: 10.3233/JAD-190897

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 403-416, 2020

Authors: Chuang, Yi-Fang | Varma, Vijay | An, Yang | Tanaka, Toshiko | Davatzikos, Christos | Resnick, Susan M. | Thambisetty, Madhav

Article Type: Research Article

Abstract: Background: An epistatic interaction between the ɛ 4 allele of apolipoprotein E (APOE ɛ 4) and the K-variant of butyrylcholinesterase (BCHE-K ) genes has been previously reported to increase risk of Alzheimer’s disease (AD). However, these observations were largely from case-control studies with small sample sizes. Objective: To examine the interaction between APOE ɛ 4 and BCHE-K on: 1) the risk of incident AD and 2) rates of change in brain volumes and cognitive performance during the preclinical stages of AD in a prospective cohort study. Methods: The study sample for survival analysis …included 691 Caucasian participants (age at baseline, 58.4±9.9 years; follow-up time,16.9±9.7 years) from the Baltimore Longitudinal Study of Aging. The neuroimaging sample included 302 participants with 1,388 brain magnetic resonance imaging (MRI) scans. Cognitive performance was assessed in 703 participants over 4,908 visits. Results: A total of 122 diagnoses (79 AD, 43 mild cognitive impairment [MCI]) were identified. Participants with both APOE ɛ 4 and BCHE-K variants had a 3.7-fold greater risk of AD (Hazard ratio [HR] 95%, CI=1.99–6.89, p  < 0.001) compared to non-carriers of both genes (APOE ɛ 4 x BCHE-K interaction p  = 0.025). There was no APOE ɛ 4-BCHE-K interaction effect on rate of cognitive decline and brain atrophy. Conclusion: The APOE and BCHE genes interact to influence risk of incident AD/MCI but not rates of brain atrophy and decline in cognitive performance before onset of cognitive impairment. This may suggest that the epistatic interaction between APOE ɛ 4 and BCHE-K on AD risk is disease stage-dependent. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E4, Butyrylcholinesterase, epistasis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-191335

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 417-427, 2020

Authors: Musaeus, Christian Sandøe | Gleerup, Helena Sophia | Høgh, Peter | Waldemar, Gunhild | Hasselbalch, Steen Gregers | Simonsen, Anja Hviid

Article Type: Research Article

Abstract: Background: Previous studies have shown an association between disruption of the blood-brain-barrier (BBB) and dementias of different etiologies. The protein concentration of cerebrospinal fluid (CSF) can be used as an indirect measurement for the permeability of the BBB using the CSF/plasma albumin quotient (Q-Alb) or total CSF protein. Objective: In the current study, we wanted to investigate Q-Alb and CSF protein concentration in dementias of different etiologies and the possible confounding factors. Methods: A total of 510 patients and healthy controls were included in the current study. The patients were diagnosed with Alzheimer’s disease (AD), dementia …with Lewy bodies (DLB), vascular dementia (VaD), or frontotemporal dementia (FTD). Results: We found that Q-Alb was significantly different between the groups (p  = 0.002, F  = 3.874). Patients with DLB and VaD showed the largest Q-Alb. Although not significant for CSF total protein, we found the same overall pattern for DLB and VaD. When examining confounding factors, we found a positive association with age and a lower Fazekas score in DLB as compared to VaD. Conclusion: These results suggest that Q-Alb can contribute to our understanding of the pathophysiological mechanisms in DLB, and Q-Alb may serve as a supplementary diagnostic marker. Furthermore, we found a positive association with age, which may be due to differences in vascular co-morbidities. In addition, in patients with DLB, the increased Q-Alb is not due to vascular lesions. Studies are needed to validate the possible diagnostic value of Q-Alb in a larger cohort. Show more

Keywords: albumin, Alzheimer’s disease, cerebrospinal fluid, CSF/plasma albumin quotient, frontotemporal dementia, Lewy body dementia, protein, Q-Alb, vascular dementia

DOI: 10.3233/JAD-200168

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 429-436, 2020

Authors: Robinson, Rebecca L. | Rentz, Dorene M. | Andrews, Jeffrey Scott | Zagar, Anthony | Kim, Yongin | Bruemmer, Valerie | Schwartz, Ronald L. | Ye, Wenyu | Fillit, Howard M.

Article Type: Research Article

Abstract: Background: Costs associated with early stages of Alzheimer’s disease (AD; mild cognitive impairment [MCI] and mild dementia [MILD]) are understudied. Objective: To compare costs associated with MCI and MILD due to AD in the United States. Methods: Data included baseline patient/study partner medical history, healthcare resource utilization, and outcome assessments as part of a prospective cohort study. Direct, indirect, and total societal costs were derived by applying standardized unit costs to resources for the 1-month pre-baseline period (USD2017). Costs/month for MCI and MILD cohorts were compared using analysis of variance models. To strengthen the confidence of …diagnosis, amyloid-β (Aβ ) tests were included and analyses were replicated stratifying within each cohort by amyloid status [+ /−]. Results: Patients (N  = 1327) with MILD versus MCI had higher total societal costs/month ($4243 versus $2816; p  < 0.001). These costs were not significantly different within each severity cohort by amyloid status. The largest fraction of overall costs were informal caregiver costs (45.1%) for the MILD cohort, whereas direct medical patient costs were the largest for the MCI cohort (39.0%). Correspondingly, caregiver time spent on basic activities of daily living (ADLs), instrumental ADLs, and supervision time was twice as high for MILD versus MCI (all p  < 0.001). Conclusion: Early AD poses a financial burden, and despite higher functioning among those with MCI, caregivers were significantly impacted. The major cost driver was the patient’s clinical cognitive-functional status and not amyloid status. Differences were primarily due to rising need for caregiver support. Show more

Keywords: Amyloid, burden of illness, dementia, economic burden, florbetapir F18, mild cognitive impairment, societal burden, H8A-US-B004, NCT02951598

DOI: 10.3233/JAD-191212

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 437-450, 2020

Authors: He, Wenting | Tu, Man | Du, Yehong | Li, Junjie | Pang, Yayan | Dong, Zhifang

Article Type: Research Article

Abstract: Background: Accumulation of amyloid-β (Aβ) peptides, generated from amyloid-β precursor protein (AβPP) amyloidogenic processing, is one of the most salient disease hallmarks of Alzheimer’s disease (AD). Nicotine is able to promote α -secretase-mediated AβPP nonamyloidogenic processing and increase the release of sAβPPα and C-terminal fragment of 83 amino acids (C83). However, the potential molecular mechanism remains elusive. Objective: The aim of the present study was to investigate the effect of nicotine on AβPP processing in SH-SY5Y cells that stably express human Swedish mutant AβPP695 (SH-SY5Y-AβPP695). Methods: The expression of AβPP and its C-terminal fragments including …C99, C89, and C83, was measured in SH-SY5Y-AβPP695 cells treated with nicotine for 6 h. Protein kinase C (PKC) antagonist Ro30-8220 or agonist PMA was used to determine the role of PKC in AβPP processing. Lentivirus-mediated shRNA targeting receptor for activated C-kinase 1 (RACK1) gene was added into the media to knockdown RACK1 expression, and then AβPP processing was examined. Results: The results showed that 6 h of nicotine exposure increased the expression of α -secretase (ADAM10) and C83 in a dose dependent manner. While the β-secretase (BACE1), AβPP amyloidogenic processing products C89 and C99 as well as Aβ peptides (including Aβ40 and Aβ42 ) remained unchanged. We also found that nicotine elevated the expression of phosphorylated PKC (P-PKC) and RACK1 on the cytomembrane. PKC antagonist Ro30-8220 treatment prevented the increase of ADAM10 and C83 by nicotine. Genetic knockdown RACK1 significantly inhibited P-PKC, and consequently abolished the increase of ADAM10 and C83 by nicotine. Conclusion: Taken together, these results indicate that nicotine effectively promotes AβPP nonamyloidogenic processing via RACK1-dependent activation of PKC in SH-SY5Y-AβPP695 cells and could be a potential molecule for AD treatment. Show more

Keywords: Alzheimer’s disease, nicotine, protein kinase C, receptor for activated C-kinase 1

DOI: 10.3233/JAD-200003

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 451-460, 2020

Authors: Zhang, Weiwei | Liu, Yiming | Bao, Hong | Zhang, Mengguo | Gao, Feng | Kang, Dongmei | Shen, Yong

Article Type: Research Article

Abstract: Background: Recent studies showed that type 2 diabetes mellitus (T2DM) may increase the risk of cognitive impairment, but there are few biomarkers to diagnostically discriminate T2DM-associated cognitive impairment and cognitive impairment alone. In this study, we assessed certain cytokines involved in inflammation and vascular diseases and identified special panel of cytokines that could differentiate between T2DM and cognitive impairment. Objective: To investigate associations and differences between T2DM and cognitive impairment by cytokines analysis. Methods: A total of 264 participants were recruited, their blood samples were collected, and plasma and serum were separated and stored at – …80°C until the assessment of amyloid-β (Aβ )42 , Aβ 40 and 8 kinds of cytokines by Luminex multiplex assays. Results: Plasma Aβ 40 is higher whereas Aβ 42/40 ratio is lower in cognitive impairment and T2DM-associated cognitive impairment compared to other groups. As compared to health control, YKL-40 level was upregulated in cognitive impairment, PRGN was downregulated in T2DM associated cognitive impairment, OPN was substantially decreased in T2DM, and IL-6 was elevated in cognitive impairment and T2DM-associated cognitive impairment. Interestingly, VEGF and S100B were induced in T2DM when compared with cognitive impairment, and NSE level in T2DM-associated cognitive impairment is significantly lower than in T2DM or cognitive impairment. Conclusion: Aβ 42 , Aβ 40 , and Aβ 42/40 ratio cannot distinguish T2DM-associated cognitive impairment from cognitive impairment. Certain cytokines (YKL-40, NSE, and VEGF) have good performance in distinguishing T2DM-associated cognitive impairment from simple cognitive impairment. Taken together, this may improve the accuracy of the diagnosis and establishment of individualized therapy. Show more

Keywords: Biomarkers, cognitive impairment, serum cytokines, type 2 diabetes mellitus

DOI: 10.3233/JAD-200095

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 461-469, 2020

Authors: Blattner, Margaret S. | Panigrahi, Sunil K. | Toedebusch, Cristina D. | Hicks, Terry J. | McLeland, Jennifer S. | Banks, Ian R. | Schaibley, Claire | Ovod, Vitaliy | Mawuenyega, Kwasi G. | Bateman, Randall J. | Wardlaw, Sharon L. | Lucey, Brendan P.

Article Type: Research Article

Abstract: Background: Concentrations of soluble amyloid-β (Aβ) oscillate with the sleep-wake cycle in the interstitial fluid of mice and cerebrospinal fluid (CSF) of humans. Further, the concentration of Aβ in CSF increases during sleep deprivation. Stress and disruption of the circadian clock are additional mechanisms hypothesized to increase CSF Aβ levels. Cortisol is a marker for stress and has an endogenous circadian rhythm. Other factors such as glucose and lactate have been associated with changes in sleep-wake activity and/or Aβ. Objective: In this exploratory study, we used samples collected in a previous study to examine how sleep deprivation affects …Aβ, cortisol, lactate, and glucose in plasma and CSF from healthy middle-aged adults (N = 11). Methods: Eleven cognitively normal participants without evidence of sleep disturbance were randomized to sleep deprivation or normal sleep control. All participants were invited to repeat the study. Cortisol, lactate, glucose, and Aβ were measured in 2-h intervals over a 36-h period in both plasma and CSF. All concentrations were normalized to the mean prior to calculating mesor, amplitude, acrophase, and other parameters. Results: One night of sleep deprivation increases the overnight concentration of Aβ in CSF approximately 10%, but does not significantly affect cortisol, lactate, or glucose concentrations in plasma or CSF between the sleep-deprived and control conditions. Conclusion: These data suggest that sleep deprivation-related changes in CSF Aβ are not mediated by stress or circadian disruption as measured by cortisol. Show more

Keywords: Amyloid-β, cortisol, sleep deprivation

DOI: 10.3233/JAD-191122

Citation: Journal of Alzheimer's Disease, vol. 75, no. 2, pp. 471-482, 2020