Journal of Alzheimer's Disease - Volume 61, issue 2

Authors: Pereira, Cátia D. | Martins, Filipa | Wiltfang, Jens | da Cruz e Silva, Odete A.B. | Rebelo, Sandra

Article Type: Review Article

Abstract: Human ATP-binding cassette (ABC) transporters mediate a critical function in the cell, namely the transport of molecules across lipid membranes. Associated to their ubiquitous tissue distribution, they are key players in cellular homeostasis but also potential causative or contributing factors for many pathologies, including Alzheimer’s disease (AD). In the central nervous system (CNS), numerous ABC transporters are present throughout the brain parenchyma and especially at the blood-brain barrier (BBB). AD is a neurodegenerative disorder mainly characterized by extracellular deposition of amyloid-β (Aβ) peptides and intracellular accumulation of hyperphosphorylated forms of tau protein. Besides being degraded via proteolytic and phagocytic processes …mediated by brain parenchymal cells, a major mechanism for eliminating cerebral Aβ is through its transport across the BBB into the peripheral blood. In fact, many AD cases are associated with impaired Aβ clearance. Consistently, several studies have recently uncovered important roles for ABC transporters in AD pathophysiology. Hence, this review focuses on the relevance of ABC transporters in CNS homeostasis by highlighting AD as a strong example of the deleterious consequences that might result from the former’s altered expression and/or activity in the brain. The potentiality of human ABC transporters as novel pharmacological targets for both the diagnosis and therapeutics of AD is emphasized. Show more

Keywords: Amyloid-β clearance, ATP-binding cassette efflux transport, blood-brain barrier, central nervous system, dementia, pharmacological modulation, therapeutic targets

DOI: 10.3233/JAD-170639

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 463-485, 2018

Authors: Tan, Chen-Chen | Zhang, Xiao-Yan | Tan, Lan | Yu, Jin-Tai

Article Type: Review Article

Abstract: Tauopathies are morphologically, biochemically, and clinically heterogeneous neurodegenerative diseases defined by the accumulation of abnormal tau proteins in the brain. There is no effective method to prevent and reverse the tauopathies, but this gloomy picture has been changed by recent research advances. Evidences from genetic studies, experimental animal models, and molecular and cell biology have shed light on the main mechanisms of the diseases. The development of radiology and biochemistry, especially the development of PET imaging, will provide important biomarkers for the clinical diagnosis and treatment. Given the central role of tau in tauopathies, many treatments have constantly emerged, including …targeting phosphorylation, targeting aggregation, increasing microtubule stabilization, tau immunization, clearance of tau, anti-inflammatory treatment, and other therapeutics. There is still a long way to go before we obtain drug therapy targeted at multifactor mechanisms. Show more

Keywords: Biomarkers, mechanisms, neurodegenerative diseases, tau, tauopathy

DOI: 10.3233/JAD-170187

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 487-508, 2018

Authors: Roe, Catherine M. | Babulal, Ganesh M. | Mishra, Shruti | Gordon, Brian A. | Stout, Sarah H. | Ott, Brian R. | Carr, David B. | Ances, Beau M. | Morris, John C. | Benzinger, Tammie L.S.

Article Type: Short Communication

Abstract: Abnormal levels of Alzheimer’s disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n  = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving …performance. Show more

Keywords: Alzheimer’s disease, amyloid, driving performance, imaging, noncognitive outcomes, tau

DOI: 10.3233/JAD-170521

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 509-513, 2018

Authors: Faxen-Irving, Gerd | Falahati, Farshad | Basun, Hans | Eriksdotter, Maria | Vedin, Inger | Wahlund, Lars-Olof | Schultzberg, Marianne | Hjorth, Erik | Palmblad, Jan | Cederholm, Tommy | Freund-Levi, Yvonne

Article Type: Short Communication

Abstract: Low tissue levels of the major marine ω 3 fatty acids (FAs) DHA and EPA are found in Alzheimer’s disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω 3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or …differences in metabolism. Show more

Keywords: Alzheimer’s disease, cognition, cohabitants, DHA, EPA, ω3 fatty acids, subcutaneous adipose tissue

DOI: 10.3233/JAD-170359

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 515-519, 2018

Authors: Synn, Artemis | Mothakunnel, Annu | Kumfor, Fiona | Chen, Yu | Piguet, Olivier | Hodges, John R. | Irish, Muireann

Article Type: Research Article

Abstract: Impaired capacity for Theory of Mind (ToM) represents one of the hallmark features of the behavioral variant of frontotemporal dementia (bvFTD) and is suggested to underpin an array of socioemotional disturbances characteristic of this disorder. In contrast, while social processing typically remains intact in Alzheimer’s disease (AD), the cognitive loading of socioemotional tasks may adversely impact mentalizing performance in AD. Here, we employed the Frith-Happé animations as a dynamic on-line assessment of mentalizing capacity with reduced incidental task demands in 18 bvFTD, 18 AD, and 25 age-matched Controls. Participants viewed silent animations in which geometric shapes interact in Random, Goal-Directed, …and ToM conditions. An exclusive deficit in ToM classification was observed in bvFTD relative to Controls, while AD patients were impaired in the accurate classification of both Random and ToM trials. Correlation analyses revealed robust associations between ToM deficits and carer ratings of affective empathy disruption in bvFTD, and with episodic memory dysfunction in AD. Voxel-based morphometry analyses further identified dissociable neural correlates contingent on patient group. A distributed network of medial prefrontal, frontoinsular, striatal, lateral temporal, and parietal regions were implicated in the bvFTD group, whereas the right hippocampus correlated with task performance in AD. Notably, subregions of the cerebellum, including lobules I-IV and V, bilaterally were implicated in task performance irrespective of patient group. Our findings reveal new insights into the mechanisms potentially mediating ToM disruption in dementia syndromes, and suggest that the cerebellum may play a more prominent role in social cognition than previously appreciated. Show more

Keywords: Cerebellum, dementia, hippocampus, medial prefrontal cortex, mentalizing, social cognition, striatum

DOI: 10.3233/JAD-170809

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 521-535, 2018

Authors: Lim, Linda | Zhang, Angeline | Lim, Levinia | Choong, Tanya-Marie | Silva, Eveline | Ng, Adeline | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: There is an increase in prevalence of young onset dementia (YOD). The specific problems among YOD patients and levels of caregiver burden (CB) in this group warrants further evaluation. Objective: To evaluate and compare level of CB in YOD and late onset dementia (LOD). Also, we sought to understand the specific factors, such as neuropsychiatric symptoms, that may affect the levels of caregiver burden in the YOD group. Methods: Patient-caregiver dyads with YOD and LOD were recruited from a tertiary neurology center. Levels of CB between YOD and LOD were compared among 183 patient-caregiver dyads. …CB was quantified using the Zarit Burden Inventory (ZBI). Neuropsychological evaluations as well as the Neuropsychiatric Inventory were performed. Factors that influenced level of CB in YOD group was investigated with regression analyses. Results: There were 57 YOD and 126 LOD dyads. Caregivers of YOD subjects reported significantly higher levels of burden compared to caregivers of LOD subjects (ZBI: 17.3 versus 13.94; p  = 0.015). 52.6% of YOD caregivers reported a high caregiver burden. When compared to caregivers of LOD, the odds of a caregiver of YOD reporting high caregiver burden was 2.34 (95% CI: 1.22–4.49: p  = 0.010). YOD dyads with a high caregiver burden had significantly higher neuropsychiatric inventory scores. Risk factors for high caregiver burden in YOD included family history of dementia and behavioral symptoms including disinhibited behavior, delusions, and apathy. Conclusion: Targeted support for caregivers of patients with YOD is needed to address the higher CB in this group. Show more

Keywords: Caregiver burden, neuropsychiatric symptoms, young onset dementia

DOI: 10.3233/JAD-170409

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 537-543, 2018

Authors: Cao, Xi | Zhu, Min | He, Yan | Chu, Wenzheng | Du, Yifeng | Du, Heng

Article Type: Research Article

Abstract: Ghrelin is a stomach-derived circulating hormone. In addition to its function as an orexigenic stimulant, the role of ghrelin in the consolidation of learning and memory has been implicated in recent years. However, the status of circulating acylated ghrelin (AG, that is, the functional form of ghrelin) in the symptomatic predementia stage of Alzheimer’s disease (AD) has rarely been investigated. In the current study, we examined the serum levels of acylated and total ghrelin in 22 patients with mild cognitive impairment (MCI) and 30 cognitively normal controls. We have found that patients with MCI had significantly increased serum AG levels, …which were inversely associated with defected short- and long-term memory as well as language skills. Of note, the levels of total circulating ghrelin were similar between the two groups. Intriguingly, serum AG but not total ghrelin was associated with AD risk factors including the age, hypertension, and hyperlipidemia. Therefore, circulating AG may serve as a potential early systemic biomarker for AD-related cognitive impairments. Nevertheless, the simplest interpretation of the results is that the levels of circulating AG are associated with cognitive impairments in patients with MCI, thereby forming the groundwork for our future studies on the systemic mechanisms of AD pertaining to the ghrelin system. Show more

Keywords: Acylated ghrelin, Alzheimer’s disease, cognitive function, ghrelin, mild cognitive impairment, risk factors

DOI: 10.3233/JAD-170721

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 545-552, 2018

Authors: Thangavel, Ramasamy | Bhagavan, Sachin M. | Ramaswamy, Swathi Beladakere | Surpur, Spurthi | Govindarajan, Raghav | Kempuraj, Duraisamy | Zaheer, Smita | Raikwar, Sudhanshu | Ahmed, Mohammad E. | Selvakumar, Govindhasamy Pushpavathi | Iyer, Shankar S. | Zaheer, Asgar

Article Type: Research Article

Abstract: Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer’s disease (AD). The E4 allele of ApoE plays a crucial role in the inflammatory and neurodegenerative processes associated with AD. This is evident from the multiple effects of the ApoE isoforms in amyloid-β (Aβ) aggregation. Glia maturation factor (GMF) is a brain-specific neuroinflammatory protein that we have previously demonstrated to be significantly upregulated in various regions of AD brains compared to non-AD control brains and that it induces neurodegeneration. We have previously reported that GMF is predominantly expressed in the reactive astrocytes surrounding amyloid plaques (APs) in AD brain. …In the present study, using immunohistochemical and dual immunofluorescence staining, we show the expression and colocalization of GMF and ApoE4 in AD brains. Our results show that ApoE4 is present within the APs of AD brain. Further, we found that GMF and ApoE4 were strongly expressed and co-associated in APs and in the reactive astrocytes surrounding APs in AD. An increased expression of GMF in APs and neurofibrillary tangles in the AD brain, and the co-localization of GMF and ApoE4 in APs suggest that GMF and ApoE4 together should be contributing to the neuropathological changes associated with AD. Show more

Keywords: Alzheimer’s disease, amyloid plaques, apolipoprotein E4, neurofibrillary tangles, neuroinflammation

DOI: 10.3233/JAD-170777

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 553-560, 2018

Authors: Yin, Xiaomin | Jiang, Xiaosu | Wang, Jia | Qian, Shuo | Liu, Fei | Qian, Wei

Article Type: Research Article

Abstract: Approximately equal amounts of 3R-tau and 4R-tau resulting from alternative splicing of tau exon 10 is necessary to maintain normal brain function. Dysregulation of alternative splicing of tau exon 10 and the imbalance of 3R-tau/4R-tau have been seen in inherited and sporadic tauopathies. Splicing factor SC35 (also name as SRSF2) plays an important role in promoting tau exon 10 inclusion. SC35 is post-translationally modified by phosphorylation and acetylation, but the role of acetylation in SC35-medicated tau exon 10 inclusion is unknown. Sirtuin type 1 (SIRT1) is an enzyme that deacetylates proteins and associates with age-related disease such as Alzheimer’s disease. …In the present study, we determined the role of SIRT1 in SC35 acetylation and in the alternative splicing of tau exon 10. We found that SIRT1 interacts with and deacetylates SC35, and inhibits SC35-promoted tau exon 10 inclusion. Substituting K52 residue of SC35 by arginine impairs the role of SC35 in tau exon 10 inclusion. These results suggest that SIRT1 may serve as a therapeutic target for tauopathy by regulating SC35-mediated tau exon 10 splicing. Show more

Keywords: alternative splicing, deacetylation, SC35, SIRT1, tau exon 10

DOI: 10.3233/JAD-170418

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 561-570, 2018

Authors: Tsou, Han-Hsing | Hsu, Wen-Chin | Fuh, Jong-Ling | Chen, Shih-Pin | Liu, Tsung-Yun | Wang, Hsiang-Tsui

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a detrimental neurodegenerative disease, and early diagnosis appears to be the key to successful treatment. Acrolein, a byproduct of lipid peroxidation, has been shown to contribute to the pathological process of AD. This study recruited 118 elderly subjects consisting of 58 non-demented control subjects and 62 AD patients. We analyzed the acrolein-related metabolites in the plasma, cerebrospinal fluid (CSF), and urine of all subjects. We found that the levels of acrolein-conjugated protein (Acr-PC) in the plasma (p  = 0.00012) and CSF (p  = 0.00161) of AD patients were significantly higher than those of control subjects, whereas the levels …of a urinary acrolein metabolite, 3-hydroxypropyl mercapturic acid (3-HPMA), were markedly decreased (p  = 0.00882) in AD patients. These data suggest that deregulated acrolein metabolism may be correlated with neuronal damage in AD patients, which might provide further insights into the disease progression and early diagnosis of AD. Show more

Keywords: Acrolein, acrolein-conjugated protein (Acr-PC), Alzheimer’s disease, 3-HPMA

DOI: 10.3233/JAD-170736

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 571-580, 2018