Journal of Alzheimer's Disease - Volume 80, issue 2

Authors: Piubelli, Luciano | Murtas, Giulia | Rabattoni, Valentina | Pollegioni, Loredano

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), the main cause of dementia worldwide, is characterized by a complex and multifactorial etiology. In large part, excitatory neurotransmission in the central nervous system is mediated by glutamate and its receptors are involved in synaptic plasticity. The N-methyl-D-aspartate (NMDA) receptors, which require the agonist glutamate and a coagonist such as glycine or the D-enantiomer of serine for activation, play a main role here. A second D-amino acid, D-aspartate, acts as agonist of NMDA receptors. D-amino acids, present in low amounts in nature and long considered to be of bacterial origin, have distinctive functions in mammals. In recent …years, alterations in physiological levels of various D-amino acids have been linked to various pathological states, ranging from chronic kidney disease to neurological disorders. Actually, the level of NMDA receptor signaling must be balanced to promote neuronal survival and prevent neurodegeneration: this signaling in AD is affected mainly by glutamate availability and modulation of the receptor’s functions. Here, we report the experimental findings linking D-serine and D-aspartate, through NMDA receptor modulation, to AD and cognitive functions. Interestingly, AD progression has been also associated with the enzymes related to D-amino acid metabolism as well as with glucose and serine metabolism. Furthermore, the D-serine and D-/total serine ratio in serum have been recently proposed as biomarkers of AD progression. A greater understanding of the role of D-amino acids in excitotoxicity related to the pathogenesis of AD will facilitate novel therapeutic treatments to cure the disease and improve life expectancy. Show more

Keywords: Amyloid-β, D-aspartate, D-serine, excitotoxicity, NMDA receptor

DOI: 10.3233/JAD-201217

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 475-492, 2021

Authors: Chalkias, Efthymios | Topouzis, Fotis | Tegos, Thomas | Tsolaki, Magda

Article Type: Review Article

Abstract: With dementia becoming increasingly prevalent, there is a pressing need to become better equipped with accurate diagnostic tools that will favorably influence its course via prompt and specific intervention. The overlap in clinical manifestation, imaging, and even pathological findings between different dementia syndromes is one of the most prominent challenges today even for expert physicians. Since cerebral microvasculature and the retina share common characteristics, the idea of identifying potential ocular biomarkers to facilitate diagnosis is not a novel one. Initial efforts included studying less quantifiable parameters such as aspects of visual function, extraocular movements, and funduscopic findings. However, the really …exciting prospect of a non-invasive, safe, fast, reproducible, and quantifiable method of pinpointing novel biomarkers has emerged with the advent of optical coherence tomography (OCT) and, more recently, OCT angiography (OCTA). The possibility of analyzing multiple parameters of retinal as well as retinal microvasculature variables in vivo represents a promising opportunity to investigate whether specific findings can be linked to certain subtypes of dementia and aid in their earlier diagnosis. The existing literature on the contribution of the eye in characterizing dementia, with a special interest in OCT and OCTA parameters will be reviewed and compared, and we will explicitly focus our effort in advancing our understanding and knowledge of relevant biomarkers to facilitate future research in the differential diagnosis between Alzheimer’s disease and common forms of cognitive impairment, including vascular dementia, frontotemporal dementia, and dementia with Lewy bodies. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, optical coherence tomography, retina

DOI: 10.3233/JAD-201516

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 493-504, 2021

Authors: Khalsa, Dharma Singh | Newberg, Andrew B.

Article Type: Review Article

Abstract: Background: Religious and spiritual interventions may have an effect on Alzheimer’s disease prevention. Kirtan Kriya meditation has been shown to mitigate the deleterious effects of chronic stress on cognition, reverse memory loss, and create psychological and spiritual wellbeing, which may reduce multiple drivers of Alzheimer’s disease risk. Objective: To detail a new concept in medicine called Spiritual Fitness, a merging of stress reduction, basic wellbeing, and psycho/spiritual wellbeing to prevent Alzheimer’s disease. Methods: The literature on the topics mentioned above is described, including an in-depth discussion on why and how each are critical to advancing the …future of Alzheimer’s disease prevention. The many negative effects of chronic stress, and the benefits of Kirtan Kriya, are reviewed. The four pillars of basic wellbeing, six practical aspects of psychological wellbeing, and the four new non-sectarian features of spiritual fitness are then disclosed. Moreover, instructions on practicing Kirtan Kriya are offered in the Supplementary Material . Conclusion: Religious and spiritual practices, including Kirtan Kriya, are crucial components in the development of enhanced cognition and well-being, which may help prevent and, in some cases, reverse cognitive decline. The key point of this review is that making a commitment to live a brain longevity lifestyle including spiritual fitness is a critically important way for aging Alzheimer’s disease free. We hope that this article will inspire scientists, clinicians, and patients to embrace this new concept of spiritual fitness and make it a part of every multidomain program for the prevention of cognitive disability. Show more

Keywords: Alzheimer’s disease prevention, kirtan kriya meditation, neurotheology, peace of mind, psychological well-being, purpose in life, spiritual fitness, spiritual well-being, spiritual/religious involvement, unlimited love

DOI: 10.3233/JAD-201433

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 505-519, 2021

Authors: Riphagen, Joost M. | van Egroo, Maxime | Jacobs, Heidi I.L.

Article Type: Short Communication

Abstract: The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer’s disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial …Alzheimer’s disease-related processes. Show more

Keywords: Amyloid-β, locus coeruleus, memory, norepinephrine, tau

DOI: 10.3233/JAD-201411

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 521-526, 2021

Authors: Brodtmann, Amy | Khlif, Mohamed Salah | Bird, Laura J. | Cumming, Toby | Werden, Emilio

Article Type: Short Communication

Abstract: Hippocampal atrophy is seen in many neurodegenerative disorders and may be a cardinal feature of vascular neurodegeneration. We examined hippocampal volume (HV) in a group of ischemic stroke survivors with amyloid 18 F-NAV4694 PET imaging three years after stroke. We compared HV between the amyloid-positive (n  = 4) and amyloid-negative (n  = 29) groups, and associations with co-morbidities using Charlson Comorbidity Indices and multi-way ANOVA. Amyloid status was not associated with verbal or visual delayed free recall memory indices or cognitive impairment. We found no association between amyloid status and HV in this group of ischemic stroke survivors.

Keywords: Amyloid imaging, atrophy, 18F-NAV4694, hippocampal volume, ischemic stroke, PET

DOI: 10.3233/JAD-201525

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 527-532, 2021

Authors: Carcavilla, Nuria | Pozo, Ana Sofía | González, Belén | Moral-Cuesta, Débora | Roldán, José Joaquín | Erice, Victoria | Remírez, Ana de Ganuza

Article Type: Short Communication

Abstract: We explored the experience from caregivers of people with dementia (PwD) during mandatory confinement due to the COVID-19 pandemic in Spain. An online survey, which studied the perceptions of the main problems and consequences experienced during confinement, was answered by 106 family caregivers of PwD. Results showed that family caregivers of PwD experienced psychological problems, like anxiety, mood, sleep, or eating disorders during confinement and felt less supported when they had to handle challenging behaviors or offer meaningful activities. An innovative multi-tiered supportive approach is needed which considers a post-pandemic reality and ensures the continuity of quality care for PwD …and their family careers. Show more

Keywords: Alzheimer’s disease, burden, caregivers, confinement, COVID-19, dementia, family careers, needs, pandemic

DOI: 10.3233/JAD-201430

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 533-537, 2021

Authors: Yu, Enyan | Liao, Zhengluan | Fan, Weixing | Hu, Weiming | Tian, Guoqiang | Chen, Ke | Chen, Sunke | Hua, Haoshui | Zheng, Hong | Fang, Xiangming | Li, Guorong | Xie, Jian | Wu, Shaochang

Article Type: Research Article

Abstract: Background: The World Alzheimer Report has described and predicted the economic burden of Alzheimer’s disease (AD) patients in detail for four consecutive years. There was a large-scale national survey in China launched by Professor Jianping Jia in 2015, but it did not adequately represent the average economic burden of AD patients in Zhejiang Province. Objective: To investigate the economic burden and main factors influencing Alzheimer’s disease (AD) in Zhejiang Province. Methods: We recruited 830 patients from 10 cities in Zhejiang Province, evaluated their per capita and total cost related to AD treatment and care in 2017, …and analyzed the main factors affecting economic burden from the perspective of demographic characteristics and disease severity. Results: In 2017, per capita cost of AD was 114,343.7 yuan, while the total cost was 27.53 billion yuan, accounting for 0.77% of Zhejiang Province’s GDP (5176.8 billion yuan). Total cost, direct medical cost, and indirect cost have different correlations with age, education level, type of work, marital status, comorbidity, and disease severity. Conclusion: The economic burden of AD in Zhejiang Province is heavy, similar to the national burden, and interventions based on demographic characteristics and disease severity can help reduce it. Show more

Keywords: Alzheimer’s disease, economic burden, influencing factors, observation research

DOI: 10.3233/JAD-201285

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 539-553, 2021

Authors: Almeida-Meza, Pamela | Steptoe, Andrew | Cadar, Dorina

Article Type: Research Article

Abstract: Background: Studies have suggested that mentally stimulating activities and socially engaged lifestyles may reduce dementia risk; however, it is unclear which activities are more beneficial. Objective: We investigated intellectual and social leisure activities in relation to dementia incidence and explored the modifying role of sex and marital status in these associations. Methods: The sample was comprised of 8,030 participants aged 50+ from the English Longitudinal Study of Ageing, who joined at wave 1 (2002-2003), or waves 3 (2006-2007), or 4 (2008-2009). The end of the study period was wave 8 (2016-2017). Subdistribution hazard models investigated the …role of leisure activities grouped into intellectual and social domains in relation to dementia while accounting for the risk of death. Subsequent analyses were conducted with individual leisure activities. Results: During the study period of up to 15 years, 412 participants developed dementia, and 2,192 died. We found that increased engagement in the intellectual activities’ domain was associated with a decreased dementia incidence (SHR 0.85, 95% CI 0.76–0.96, p  = 0.007), independent of the risk of death in married individuals, but not in those who were single, divorced, or widowed. Individual analyses for each leisure activity showed independent associations for reading newspapers in females (SHR 0.65, 95% CI 0.49–0.84, p  = 0.001), mobile phone usage in males (SHR 0.61, 95% CI 0.45–0.84, p  = 0.002), and having hobbies for married individuals (SHR 0.70, 95% CI 0.51–0.95, p  = 0.02). Conclusion: We found that intellectual leisure activities contribute to lower dementia risk in a representative population of English adults, suggesting intervention opportunities. Show more

Keywords: Cognitive reserve, dementia, intellectual, leisure activities, longitudinal study, social, subdistribution hazard model

DOI: 10.3233/JAD-200952

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 555-565, 2021

Authors: Han, Fei | Zhai, Fei-Fei | Li, Ming-Li | Zhou, Li-Xin | Ni, Jun | Yao, Ming | Jin, Zheng-Yu | Cui, Li-Ying | Zhang, Shu-Yang | Zhu, Yi-Cheng

Article Type: Research Article

Abstract: Background: Mechanisms through which arterial stiffness impacts cognitive function are crucial for devising better strategies to prevent cognitive decline. Objective: To examine the associations of arterial stiffness with white matter integrity and cognition in community dwellings, and to investigate whether white matter injury was the intermediate of the associations between arterial stiffness and cognition. Methods: This study was a cross-sectional analysis on 952 subjects (aged 55.5±9.1 years) who underwent diffusion tensor imaging and measurement of brachial-ankle pulse wave velocity (baPWV). Both linear regression and tract-based spatial statistics were used to investigate the association between baPWV and …white matter integrity. The association between baPWV and global cognitive function, measured as the mini-mental state examination (MMSE) was evaluated. Mediation analysis was performed to assess the influence of white matter integrity on the association of baPWV with MMSE. Results: Increased baPWV was significantly associated with lower mean global fractional anisotropy (β= –0.118, p  < 0.001), higher mean diffusivity (β= 0.161, p  < 0.001), axial diffusivity (β= 0.160, p  < 0.001), and radial diffusivity (β= 0.147, p  < 0.001) after adjustment of age, sex, and hypertension, which were measures having a direct effect on arterial stiffness and white matter integrity. After adjustment of age, sex, education, apolipoprotein E ɛ 4, cardiovascular risk factors, and brain atrophy, we found an association of increased baPWV with worse performance on MMSE (β= –0.093, p  = 0.011). White matter disruption partially mediated the effect of baPWV on MMSE. Conclusion: Arterial stiffness is associated with white matter disruption and cognitive decline. Reduced white matter integrity partially explained the effect of arterial stiffness on cognition. Show more

Keywords: Arterial stiffness, brachial-ankle pulse wave velocity, cognitive function, diffusion tensor imaging, white matter

DOI: 10.3233/JAD-201424

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 567-576, 2021

Authors: Yao, Weina | Chen, Haifeng | Luo, Caimei | Sheng, Xiaoning | Zhao, Hui | Xu, Yun | Bai, Feng | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Self-referential processing is associated with the progression of Alzheimer’s disease (AD), and cerebrospinal fluid (CSF) proteins have become accepted biomarkers of AD. Objective: Our objective in this study was to focus on the relationships between the self-referential network (SRN) and CSF pathology in AD-spectrum patients. Methods: A total of 80 participants, including 20 cognitively normal, 20 early mild cognitive impairment (EMCI), 20 late MCI (LMCI), and 20 AD, were recruited for this study. Independent component analysis was used to explore the topological SRN patterns, and the abnormalities of this network were identified at different stages …of AD. Finally, CSF pathological characteristics (i.e., CSF Aβ, t-tau, and p-tau) that affected the abnormalities of the SRN were further determined during the progression of AD. Results: Compared to cognitively normal subjects, AD-spectrum patients (i.e., EMCI, LMCI, and AD) showed a reversing trend toward an association between CSF pathological markers and the abnormal SRN occurring during the progression of AD. However, a certain disease state (i.e., the present LMCI) with a low concentration of CSF tau could evoke more hyperconnectivity of the SRN than other patients with progressively increasing concentrations of CSF tau (i.e., EMCI and AD), and this fluctuation of CSF tau was more sensitive to the hyperconnectivity of the SRN than the dynamic changes of CSF Aβ. Conclusion: The integrity of the SRN was closely associated with CSF pathological characteristics, and these findings support the view that the hyperconnectivity of the SRN will play an important role in monitoring the progression of the pre-dementia state to AD. Show more

Keywords: Alzheimer’s disease spectrum patients, cerebrospinal fluid pathology, functional connectivity, hyperconnectivity, self-referential network

DOI: 10.3233/JAD-201376

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 577-590, 2021