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

Authors: Tsamou, Maria | Pistollato, Francesca | Roggen, Erwin L.

Article Type: Research Article

Abstract: The worldwide prevalence of sporadic (late-onset) Alzheimer’s disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss …is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aβ-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, environmental impact, memory loss, neurotoxicity, tauopathy

DOI: 10.3233/JAD-201418

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-27, 2021

Authors: Halminen, Olli | Vesikansa, Aino | Mehtälä, Juha | Hörhammer, Iiris | Mikkola, Teija | Virta, Lauri J. | Ylisaukko-oja, Tero | Linna, Miika

Article Type: Research Article

Abstract: Background: Dementia is one of the strongest predictors of admission to a 24-hour care facility among older people, and 24-hour care is the major cost of Alzheimer’s disease (AD). Objective: The aim of this study was to evaluate the association of early start of anti-dementia medication and other predisposing factors with 2-year risk of transition to 24-hour care in the nationwide cohort of Finnish AD patients. Methods: This was a retrospective, non-interventional study based on individual-level data from Finnish national health and social care registers. The incident cohort included 7,454 AD patients (ICD-10, G30) comprised of …two subgroups: those living unassisted at home (n  = 5,002), and those receiving professional home care (n  = 2,452). The primary outcome was admission to a 24-hour care facility. Exploratory variables were early versus late anti-dementia medication start, sociodemographic variables, care intensity level, and comorbidities. Results: Early anti-dementia medication reduced the risk of admission to 24-hour care both in patients living unassisted at home, with a hazard ratio (HR) of 0.58 (p  <  0.001), and those receiving professional home care (HR, 0.84; p  = 0.039). Being unmarried (HR, 1.69; p  <  0.001), having an informal caregiver (HR, 1.69; p  = 0.003), or having a diagnosis of additional neurological disorder (HR, 1.68; p  = 0.006) or hip fracture (HR, 1.61; p  = 0.004) were associated with higher risk of admission to 24-hour care in patients living unassisted at home. Conclusion: To support living at home, early start of anti-dementia medication should be a high priority in newly diagnosed AD patients. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, dementia, finland, healthcare, institutionalization, memantine, nursing homes, register

DOI: 10.3233/JAD-201502

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Eeza, Muhamed N.H. | Singer, Rico | Höfling, Corinna | Matysik, Jörg | de Groot, Huub J.M. | Roβner, Steffen | Alia, A.

Article Type: Research Article

Abstract: Background: Circadian rhythm disturbance is commonly observed in Alzheimer’s disease (AD). In mammals, these rhythms are orchestrated by the superchiasmatic nucleus (SCN). Our previous study in the Tg2576 AD mouse model suggests that inflammatory responses, most likely manifested by low GABA production, may be one of the underlying perpetrators for the changes in circadian rhythmicity and sleep disturbance in AD. However, the mechanistic connections between SCN dysfunction, GABA modulation, and inflammation in AD is not fully understood. Objective: To reveal influences of amyloid pathology in Tg2576 mouse brain on metabolism in SCN and to identify key metabolic sensors …that couple SCN dysfunction with GABA modulation and inflammation. Methods: High resolution magic angle spinning (HR-MAS) NMR in conjunction with multivariate analysis was applied for metabolic profiling in SCN of control and Tg2576 female mice. Immunohistochemical analysis was used to detect neurons, astrocytes, expression of GABA transporter 1 (GAT1) and Bmal1 . Results: Metabolic profiling revealed significant metabolic deficits in SCN of Tg2576 mice. Reductions in glucose, glutamate, GABA, and glutamine provide hints toward an impaired GABAergic glucose oxidation and neurotransmitter cycling in SCN of AD mice. In addition, decreased redox co-factor NADPH and glutathione support a redox disbalance. Immunohistochemical examinations showed low expression of the core clock gene, Bmal1 , especially in activated astrocytes. Moreover, decreased expression of GAT1 in astrocytes indicates low GABA recycling in this cell type. Conclusion: Our results suggest that redox disbalance and compromised GABA signaling are important denominators and connectors between neuroinflammation and clock dysfunction in AD. Show more

Keywords: Alzheimer’s disease, GABA dysfunction, 1H high-resolution magic angle spinning NMR, metabolic deficit, suprachiasmatic nucleus, Tg2576 mouse model

DOI: 10.3233/JAD-201575

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Wang, Ziqi | Zhang, Yige | Dong, Li | Zheng, Zihao | Zhong, Dayong | Long, Xunqin | Cai, Qingyan | Jian, Wei | Zhang, Songge | Wu, Wenbin | Yao, Dezhong

Article Type: Research Article

Abstract: Background: Given that there is no specific drug to treat Alzheimer’s disease, non-pharmacologic interventions in people with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are one of the most important treatment strategies. Objective: To clarify the efficacy of blue-green (500 nm) light therapy on sleep, mood, and physiological parameters in patients with SCD and aMCI is an interesting avenue to explore. Methods: This is a monocentric, randomized, and controlled trial that will last for 4 weeks. We will recruit 150 individuals aged 45 years or older from memory clinics and divide them into 5 …groups: SCD treatment (n  = 30), SCD control (n  = 30), aMCI treatment (n  = 30), aMCI control (n  = 30), and a group of healthy adult subjects (n  = 30) as a normal control (NC). Results: The primary outcome is the change in subjective and objective cognitive performance between baseline and postintervention visits (4 weeks after baseline). Secondary outcomes include changes in performance assessing from baseline, postintervention to follow-up (3 months after the intervention), as well as sleep, mood, and physiological parameters (including blood, urine, electrophysiology, and neuroimaging biomarkers). Conclusion: This study aims to provide evidence of the impact of light therapy on subjective and objective cognitive performance in middle-aged and older adults with SCD or aMCI. In addition, we will identify possible neurophysiological mechanisms of action underlying light therapy. Overall, this trial will contribute to the establishment of light therapy in the prevention of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, low-level light therapy, non-pharmacologic interventions, phototherapy

DOI: 10.3233/JAD-201560

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Mizuno, Akiko | Karim, Helmet T. | Ly, Maria J. | Cohen, Ann D. | Lopresti, Brian J. | Mathis, Chester A. | Klunk, William E. | Aizenstein, Howard J. | Snitz, Beth E.

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer’s disease. Elevated amyloid-β (Aβ) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aβ is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates. Objective: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aβ, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations. Methods: We …measured brain activation during the “face-name” memory-encoding fMRI task and Aβ deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n = 63, mean age 73.1 ± 7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aβ, and interactions with education. Results: Activation was not directly associated with SCD symptoms or Aβ. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education. Conclusion: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve. Show more

Keywords: Amyloid, cognitive reserve, functional MRI, PiB-PET, preclinical dementia, subjective cognitive decline

DOI: 10.3233/JAD-201087

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Suh, Seung Wan | Kim, You Joung | Kwak, Kyung Phil | Kim, Kiwon | Kim, Moon-Doo | Kim, Byung-Soo | Kim, Bong Jo | Kim, Shin Gyeom | Kim, Jeong Lan | Kim, Tae Hui | Moon, Seok Woo | Park, Kyung Won | Park, Jong-Il | Park, Joon Hyuk | Bae, Jae Nam | Seo, Jiyeong | Seong, Su Jeong | Son, Sang Joon | Shin, Il-Seon | Ryu, Seung-Ho | Lee, Kang Joon | Lee, Nam-Jin | Lee, Dong Young | Lee, Dong Woo | Lee, Seok Bum | Lee, Chang Uk | Chang, Sung Man | Jeong, Hyun-Ghang | Cho, Maeng Je | Cho, Seong-Jin | Jhoo, Jin Hyeong | Choe, Young Min | Han, Ji Won | Kim, Ki Woong

Article Type: Research Article

Abstract: Background: In many high-income Western countries, the prevalence of dementia had been reduced over the past decades. Objective: We investigated whether the prevalence of all-cause dementia, Alzheimer’s disease, vascular dementia, and mild cognitive impairment (MCI) had changed in Korea from 2008 to 2017. Methods: Nationwide Survey on Dementia Epidemiology of Korea (NaSDEK) in 2008 and 2017 was conducted on representative elderly populations that were randomly sampled across South Korea. Both surveys employed a two-stage design (screening and diagnostic phases) and diagnosed dementia and MCI according to the fourth edition of the Diagnostic and Statistical Manual of …Mental Disorders and the consensus criteria from the International Working Group, respectively. The numbers of participants aged 65 years or older in the screening and diagnostic phases were 6,141 and 1,673 in the NaSDEK 2008 and 2,972 and 474 in the NaSDEK 2017, respectively. Results: The age- and sex-standardized prevalence of all-cause dementia and Alzheimer’s disease showed nonsignificant decrease (12.3% to 9.8%, odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.54–1.48 for all-cause dementia; 7.6% to 6.8%, OR [95% CI] = 0.91 [0.58–1.42] for Alzheimer’s disease). Vascular dementia decreased in the young-old population aged less than 75 years (2.7% to 0.001%, OR [95% CI] = 0.04 [0.01–0.15]) and in women (1.9% to 0.5%, OR [95% CI] = 0.27 [0.10–0.72]) while MCI remained stable (25.3% to 26.2%, OR [95% CI] = 1.08 [0.67–1.73]). Conclusion: We found that the prevalence of dementia in Korea showed a nonsignificant decrease between 2008 and 2017. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, prevalence, vascular dementia

DOI: 10.3233/JAD-201588

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Manuel Gómez-López, Vıctor | Viramontes-Pintos, Amparo | Ontiveros-Torres, Miguel Ángel | Garcés-Ramírez, Linda | de la Cruz, Fidel | Villanueva-Fierro, Ignacio | Bravo-Muñoz, Marely | Harrington, Charles R. | Martínez-Robles, Sandra | Yescas, Petra | Guadarrama-Ortíz, Parménides | Hernándes-Alejandro, Mario | Montiel-Sosa, Francisco | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc ) of a normal cellular protein (PrPC ) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC , and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer’s disease (AD). In …AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers of the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to the toxic and inflammatory environment generated by the pathological form of prion. Show more

Keywords: Cerebellum, neuronal death, prion encephalopathy, prion protein, tau protein

DOI: 10.3233/JAD-201308

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Marra, Camillo | Piccininni, Chiara | Iacobucci, Giovanna Masone | Caprara, Alessia | Gainotti, Guido | Maria Costantini, Emanuele | Callea, Antonio | Venneri, Annalena | Quaranta, Davide

Article Type: Research Article

Abstract: Background: The assessment of semantic memory may be a useful marker to identify individuals with mild cognitive impairment (MCI) who will progress to Alzheimer’s disease (AD) in the early stages of the disease. Objective: The aim of this five-year follow-up longitudinal study is to assess whether semantic assessment could predict progression in MCI. Methods: A population of MCI (N = 251); mild (N = 178) and moderate AD (N = 114); and a sample of healthy participants (HP; N = 262) was investigated. The five-year follow-up of the MCI group was completed by 178 patients. Semantic and episodic memory measures were used, including a …measure of the discrepancy between categorical and phonological verbal fluency, the semantic–phonological delta (SPD). The main outcome was the progression of MCI due to AD to dementia. Results: A general linear model showed a significant effect of diagnosis on SPD (Wilks’ Lambda = 0.591; p  <  0.001). The estimated marginal means were –0.91 (SE = 0.185) in HP, –1.83 (SE = 0.187) in MCI, –1.16 (SE = 0.218) in mild AD, and –1.02 (SE = 0.275) in moderate AD. Post-hoc comparisons showed a significant difference between MCI and HP (p  <  0.001). The follow-up was completed by 178 MCI individuals. SPD in MCI patients who progress to dementia was significantly lower than in MCI that will not progress (p  = 0.003). Together with the Mini-Mental State Examination, the SPD was the only measure with a significant predicting effect at the five-years follow-up (p  = 0.016). Conclusion: The SPD indicate the impairment of semantic memory in individuals with underlying AD at the MCI early stage, reflecting the early involvement of perirhinal and entorhinal cortices in the earliest stages of AD neuropathological process. Show more

Keywords: Alzheimer’s disease, category fluency task, memory, mild cognitive impairment

DOI: 10.3233/JAD-201452

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Hashimoto, Makoto | Ho, Gilbert | Sugama, Shuei | Takenouchi, Takato | Waragai, Masaaki | Sugino, Hiromu | Inoue, Satoshi | Masliah, Eliezer

Article Type: Research Article

Abstract: Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer’s disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of …APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ 42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target. Show more

Keywords: Activin, adiponectin paradox, Alzheimer’s disease, amyloidogenic proteins, antagonistic pleiotropy, evolvability, transforming growth factor β

DOI: 10.3233/JAD-210206

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Taylor, Morag E. | Toots, Annika | Lord, Stephen R. | Payne, Narelle | Close, Jacqueline C.T.

Article Type: Research Article

Abstract: Background: In older people with cognitive impairment (CI), executive function (EF) has been associated with motor performance including balance and gait. The literature examining and supporting a relationship between balance performance and other cognitive domains is limited. Objective: To investigate the relationship between global cognition and cognitive domain function and balance performance in older people with CI. Methods: The iFOCIS randomized controlled trial recruited 309 community-dwelling older people with CI. Baseline assessments completed before randomization were used for analyses including the Addenbrooke’s Cognitive Examination-III (ACE-III; global cognition) and its individual cognitive domains (attention; memory; verbal …fluency; language; visuospatial ability) and the Frontal Assessment Battery (FAB), a measure of EF. A composite balance score was derived from postural sway and leaning balance tests. Results: In linear regression analyses adjusted for covariates, global cognition and each cognitive domain were significantly associated with balance performance. EF (verbal fluency; β= –0.254, p  <  0.001, adjusted R2  = 0.387) and visuospatial ability (β= –0.258, p  <  0.001, adjusted R2  = 0.391) had the strongest associations with balance performance. In a comprehensively adjusted multivariable model including all of the ACE-III cognitive domains, visuospatial ability and EF (verbal fluency) were independently and significantly associated with balance performance. Conclusion: Poorer global cognition and cognitive domain function were associated with poorer balance performance in this sample of people with CI. Visuospatial ability and EF were independently associated with balance, highlighting potential shared neural networks and the role higher-level cognitive processes and spatial perception/processing play in postural control. Show more

Keywords: Aged, cognition, dementia, executive function, postural control, visuospatial

DOI: 10.3233/JAD-201325

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021