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Cover Illustration
2016, Vol.7  No.3
Figure. The effect of age on cortical thickness in healthy Ccontrols and Parkinson’s disease. Green highlighted regions represent those regions that follow a linear rate of atrophy. Red highlighted regions depict rates of early decline (decreasing quickly at first, then stabilizing), while regions in yellow depict regions that atrophy faster over time (stable at first, then decreasing quickly). Regions in orange depict early decline, stabilization, followed by late decline, which is notable in later decades of life (early-stable-late). PD patients show characteristic frontal cortical thinning with age. Regions in yellow depict regions that atrophy faster over ti [Detail] ...

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  • Table of Content
      09 January 2016, Volume 7 Issue 3 Previous Issue    Next Issue
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    Letter to the Editor/Erratum
    Question Marks Left Over a Quantitative Assessment of Apolipoprotein C3 Gene Polymorphisms
    Sand Philipp G.
    Aging and disease. 2016, 7 (3): 216-219.   DOI: 10.14336/AD.2016.0502
    Abstract   HTML   PDF (567KB) ( 841 )
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    Original Article
    Linear and Curvilinear Trajectories of Cortical Loss with Advancing Age and Disease Duration in Parkinson’s Disease
    Claassen Daniel O., Dobolyi David G., Isaacs David A., Roman Olivia C., Herb Joshua, Wylie Scott A., Neimat Joseph S., Donahue Manus J., Hedera Peter, Zald David H., Landman Bennett A., Bowman Aaron B., Dawant Benoit M., Rane Swati
    Aging and disease. 2016, 7 (3): 220-229.   DOI: 10.14336/AD.2015.1110
    Abstract   HTML   PDF (1013KB) ( 1666 )

    Advancing age and disease duration both contribute to cortical thinning in Parkinson’s disease (PD), but the pathological interactions between them are poorly described. This study aims to distinguish patterns of cortical decline determined by advancing age and disease duration in PD. A convenience cohort of 177 consecutive PD patients, identified at the Vanderbilt University Movement Disorders Clinic as part of a clinical evaluation for Deep Brain Stimulation (age: M= 62.0, SD 9.3), completed a standardized clinical assessment, along with structural brain Magnetic Resonance Imaging scan. Age and gender matched controls (n=53) were obtained from the Alzheimer Disease Neuroimaging Initiative and Progressive Parkinson’s Marker Initiative (age: M= 63.4, SD 12.2). Estimated changes in cortical thickness were modeled with advancing age, disease duration, and their interaction. The best-fitting model, linear or curvilinear (2nd, or 3rd order natural spline), was defined using the minimum Akaike Information Criterion, and illustrated on a 3-dimensional brain. Three curvilinear patterns of cortical thinning were identified: early decline, late decline, and early-stable-late. In contrast to healthy controls, the best-fit model for age related changes in PD is curvilinear (early decline), particularly in frontal and precuneus regions. With advancing disease duration, a curvilinear model depicts accelerating decline in the occipital cortex. A significant interaction between advancing age and disease duration is evident in frontal, motor, and posterior parietal areas. Study results support the hypothesis that advancing age and disease duration differentially affect regional cortical thickness and display regional dependent linear and curvilinear patterns of thinning.

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    Effect of a Leucine-rich Repeat Kinase 2 Variant on Motor and Non-motor Symptoms in Chinese Parkinson’s Disease Patients
    Sun Qian, Wang Tian, Jiang Tian-Fang, Huang Pei, Li Dun-Hui, Wang Ying, Xiao Qin, Liu Jun, Chen Sheng-Di
    Aging and disease. 2016, 7 (3): 230-236.   DOI: 10.14336/AD.2015.1026
    Abstract   HTML   PDF (845KB) ( 2339 )

    The G2385R variant of the leucine-rich repeat kinase 2 (LRRK2) is strongly associated with Parkinson’s disease (PD) in Asian populations. However, it is still unclear whether the clinical phenotype of PD patients with the G2385R variant can be distinguished from that of patients with idiopathic PD. In this study, we investigated motor and non-motor symptoms of LRRK2 G2385R variant carriers in a Chinese population. We genotyped 1031 Chinese PD patients for the G2385R variant of the LRRK2 gene, and examined the demographic and clinical characteristics of LRRK2 G2385R variant carrier and non-carrier PD patients. LRRK2 G2385R variant carriers were more likely to present the postural instability and gait difficulty dominant (PIGD) phenotype. This variant was also significantly associated with motor fluctuations and the levodopa equivalent dose (LED). G2385R variant carriers had higher REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) score and more RBD symptoms compared with non-carriers. We concluded that the G2385R variant could be a risk factor for the PIGD phenotype, motor fluctuations, LED values and RBD symptoms.

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    Higher Plasma LDL-Cholesterol is Associated with Preserved Executive and Fine Motor Functions in Parkinson’s Disease
    Sterling Nicholas W., Lichtenstein Maya, Lee Eun-Young, Lewis Mechelle M., Evans Alicia, Eslinger Paul J., Du Guangwei, Gao Xiang, Chen Honglei, Kong Lan, Huang Xuemei
    Aging and disease. 2016, 7 (3): 237-245.   DOI: 10.14336/AD.2015.1030
    Abstract   HTML   PDF (817KB) ( 2015 )

    Plasma low density lipoprotein (LDL) cholesterol has been associated both with risk of Parkinson’s disease (PD) and with age-related changes in cognitive function. This prospective study examined the relationship between baseline plasma LDL-cholesterol and cognitive changes in PD and matched Controls. Fasting plasma LDL-cholesterol levels were obtained at baseline from 64 non-demented PD subjects (62.7 ± 7.9 y) and 64 Controls (61.3 ± 6.8 y). Subjects underwent comprehensive neuropsychological testing at baseline, 18-, and 36-months. Linear mixed-effects modeling was used to assess the relationships between baseline LDL-cholesterol levels and longitudinal cognitive changes. At baseline, PD patients had lower scores of fine motor (p<0.0001), executive set shifting (p=0.018), and mental processing speed (p=0.049) compared to Controls. Longitudinally, Controls demonstrated improved fine motor and memory test scores (p=0.044, and p=0.003), whereas PD patients demonstrated significantly accelerated loss in fine motor skill (p=0.002) compared to Controls. Within the PD group, however, higher LDL-cholesterol levels were associated with improved executive set shifting (β=0.003, p<0.001) and fine motor scores (β=0.002, p=0.030) over time. These associations were absent in Controls (p>0.7). The cholesterol - executive set shifting association differed significantly between PDs and Controls (interaction p=0.005), whereas the cholesterol - fine motor association difference did not reach significance (interaction, p=0.104). In summary, higher plasma LDL-cholesterol levels were associated with better executive function and fine motor performance over time in PD, both of which may reflect an effect on nigrostriatal mediation. Confirmation of these results and elucidation of involved mechanisms are warranted, and might lead to feasible therapeutic strategies.

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    Predictors of Difficulty in Medication Intake in Europe: a Cross-country Analysis Based on SHARE
    Figueiredo Daniela, Teixeira Laetitia, Poveda Veronica, Paúl Constança, Santos-Silva Alice, Costa Elísio
    Aging and disease. 2016, 7 (3): 246-253.   DOI: 10.14336/AD.2015.0925
    Abstract   HTML   PDF (679KB) ( 776 )

    The aim of this study is to evaluate the prevalence and the predictors of difficulty in medication intake across Europe, using a cross-sectional design. We used data from all participants in the wave 4 of the SHARE (Survey of Health, Ageing, and Retirement in Europe) database, which is a cross national European survey. The difficulty in take medication was evaluated using an item from the “Limitations with activities of daily living”. Clinical and sociodemographic variables were evaluated as potential predictors. A total of 58 124 individual have been included in this work (mean age=64.9 ± 10.4 years; 43.3% male). The rate of difficulty in taking medication across the 16 European evaluated countries was 2.1%, presenting Spain the highest rate (5.7%) and Switzerland the lowest (0.6%). Increasing age, physical inactivity, physical limitations (mobility, arms function and fine motor limitations, and difficulties in picking up a small coin from a table), a poor sense of meaning in life, and losses in memory and concentration are independent and significant variables associated with difficulty in medication intake across Europe. Predictors of difficulties in medication intake are multicausal, including factors related to physical, cognitive and psychological conditions. Interventions aiming to optimize adherence to medication, particularly in elderly population, need to consider this diversity of determinants.

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    Failure of Elevating Calcium Induces Oxidative Stress Tolerance and Imparts Cisplatin Resistance in Ovarian Cancer Cells
    Ma Liwei, Wang Hongjun, Wang Chunyan, Su Jing, Xie Qi, Xu Lu, Yu Yang, Liu Shibing, Li Songyan, Xu Ye, Li Zhixin
    Aging and disease. 2016, 7 (3): 254-266.   DOI: 10.14336/AD.2016.0118
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    Cisplatin is a commonly used chemotherapeutic drug, used for the treatment of malignant ovarian cancer, but acquired resistance limits its application. There is therefore an overwhelming need to understand the mechanism of cisplatin resistance in ovarian cancer, that is, ovarian cancer cells are insensitive to cisplatin treatment. Here, we show that failure of elevating calcium and oxidative stress tolerance play key roles in cisplatin resistance in ovarian cancer cell lines. Cisplatin induces an increase in oxidative stress and alters intracellular Ca2+ concentration, including cytosolic and mitochondrial Ca2+ in cisplatin-sensitive SKOV3 cells, but not in cisplatin-resistant SKOV3/DDP cells. Cisplatin induces mitochondrial damage and triggers the mitochondrial apoptotic pathway in cisplatin-sensitive SKOV3 cells, but rarely in cisplatin-resistant SKOV3/DDP cells. Inhibition of calcium signaling attenuates cisplatin-induced oxidative stress and intracellular Ca2+ overload in cisplatin-sensitive SKOV3 cells. Moreover, in vivo xenograft models of nude mouse, cisplatin significantly reduced the growth rates of tumors originating from SKOV3 cells, but not that of SKOV3/DDP cells. Collectively, our data indicate that failure of calcium up-regulation mediates cisplatin resistance by alleviating oxidative stress in ovarian cancer cells. Our results highlight potential therapeutic strategies to improve cisplatin resistance.

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    Proteolytic Cleavage of Apolipoprotein E in the Down Syndrome Brain
    Day Ryan J., McCarty Katie L., Ockerse Kayla E., Head Elizabeth, Rohn Troy T.
    Aging and disease. 2016, 7 (3): 267-277.   DOI: 10.14336/AD.2015.1020
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    Down syndrome (DS) is one of the most common genetic causes of intellectual disability and is characterized by a number of behavioral as well as cognitive symptoms. Many of the neuropathological features of early-onset Alzheimer’s disease (AD) including senile plaques and neurofibrillary tangles (NFTs) are also present in people with DS as a result of triplication of the amyloid precursor gene on chromosome 21. Evidence suggests that harboring one or both apolipoprotein E4 (APOE4) alleles may increase the risk for AD due to the proteolytic cleavage of apoE4 and a subsequent loss of function. To investigate a role for the apoE proteolysis in vivo, we compared three autopsy groups; 7 DS with AD neuropathology cases over 40 years, 5 young DS cases without AD pathology under 40 years (YDS) and 5 age-matched control cases over 40 years by immunohistochemistry utilizing an antibody that detects the amino-terminal fragment of apoE. Application of this antibody, termed the amino-terminal apoE fragment antibody (nApoECF) revealed labeling of pyramidal neurons in the frontal cortex of YDS cases, whereas in the DS-AD group, labeling with nApoECF was prominent within NFTs. NFT labeling with nApoECF was significantly greater in the hippocampus versus the frontal cortex in the same DS-AD cases, suggesting a regional distribution of truncated apoE. Colocalization immunofluorescence experiments indicated that 52.5% and 53.2% of AT8- and PHF-1-positive NFTs, respectively, also contained nApoECF. Collectively, these data support a role for the proteolytic cleavage of apoE in DS and suggest that apoE fragmentation is closely associated with NFTs.

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    Levels and Rates of Physical Activity in Older Adults with Multiple Sclerosis
    Klaren Rachel E., Sebastiao Emerson, Chiu Chung-Yi, Kinnett-Hopkins Dominique, McAuley Edward, Motl Robert W.
    Aging and disease. 2016, 7 (3): 278-284.   DOI: 10.14336/AD.2015.1025
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    There is much evidence supporting the safety and benefits of physical activity in adults with multiple sclerosis (MS) and recent evidence of beneficial effects on physical function in older adults with MS. However, there is very little known about physical activity participation in older adults with conditions such as MS. This study compared levels of physical activity (i.e., sedentary behavior, light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA)) and rates of meeting public health guidelines for MVPA (i.e., ≥30 min/day) among young (i.e., ages 20-39 years), middle-aged (i.e., ages 40-59 years) and older adults (i.e., ages ≥60 years) with MS. The sample included 963 persons with MS who provided demographic and clinical information and wore an accelerometer for a 7-day period. The primary analysis involved a between-subjects ANOVA on accelerometer variables (i.e., accelerometer wear time; number of valid days; sedentary behavior in min/day; LPA in min/day; and MVPA in min/day). Collectively, our data indicated that older adults with MS engaged in less MVPA and more sedentary behavior than middle-aged and young adults with MS. Such results highlight the importance of developing physical activity interventions as an effective means for managing the progression and consequences of MS in older adults.

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    Successful Aging among Elders Living in the Mani Continental Region vs. Insular Areas of the Mediterranean: the MEDIS Study
    Mariolis Anargiros, Foscolou Alexandra, Tyrovolas Stefanos, Piscopo Suzanne, Valacchi Giuseppe, Tsakountakis Nikos, Zeimbekis Akis, Bountziouka Vassiliki, Gotsis Efthimios, Metallinos George, Tyrovola Dimitra, Tur Josep-Antoni, Matalas Antonia-Leda, Lionis Christos, Polychronopoulos Evangelos, Panagiotakos Demosthenes, for the MEDIS study group
    Aging and disease. 2016, 7 (3): 285-294.   DOI: 10.14336/AD.2015.1002
    Abstract   HTML   PDF (937KB) ( 1220 )

    To evaluate the role of geography i.e., continental vs. insular Mediterranean, on successful aging among older inhabitants. During 2005-2014, 2693 elderly (aged 65 to 100 years) individuals from 21 Mediterranean islands in Greece, Italy and Spain as well as Cyprus, Malta, and the rural region of Mani (southeast continental region of Greece keeping old-time traditions), were voluntarily recruited. Successful aging was evaluated using a validated index composed of 10 health-related socio-lifestyle and clinical characteristics. After accounting for age, sex, body mass index (BMI), physical activity, smoking habits, MedDietScore and access to health care services, the older inhabitants of islands were found to have a higher level of the successful aging index when compared to their counterparts in Mani (Beta=0.174, p<0.001); moreover, islanders exhibited slightly more years of “good” health (68.7 vs 68.4 years for Mani residents (p=0.99)). However, compared to the residents of Mani, islanders had 1.64 times higher odds (95%CI, 1.08-2.48) for having hypertension, 2.4-times higher odds (95%CI, 1.34-4.21) for having diabetes and 1.52 times higher odds (95%CI, 0.97-2.38) for having hypercholesterolemia. Engaging in physical activities and healthy dietary habits were the major determinants of healthy aging, among islanders as compared to their counterparts of continental Mani region. Elder residents of the continental Mani area enjoyed a better health status, whereas elder islanders had a higher level of successful aging; a finding which could be attributed to differences in lifestyle among elders.

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    Review Article
    Epigenetic Regulation of Oxidative Stress in Ischemic Stroke
    Zhao Haiping, Han Ziping, Ji Xunming, Luo Yumin
    Aging and disease. 2016, 7 (3): 295-306.   DOI: 10.14336/AD.2015.1009
    Abstract   HTML   PDF (966KB) ( 1787 )

    The prevalence and incidence of stroke rises with life expectancy. However, except for the use of recombinant tissue-type plasminogen activator, the translation of new therapies for acute stroke from animal models into humans has been relatively unsuccessful. Oxidative DNA and protein damage following stroke is typically associated with cell death. Cause-effect relationships between reactive oxygen species and epigenetic modifications have been established in aging, cancer, acute pancreatitis, and fatty liver disease. In addition, epigenetic regulatory mechanisms during stroke recovery have been reviewed, with focuses mainly on neural apoptosis, necrosis, and neuroplasticity. However, oxidative stress-induced epigenetic regulation in vascular neural networks following stroke has not been sufficiently explored. Improved understanding of the epigenetic regulatory network upon oxidative stress may provide effective antioxidant approaches for treating stroke. In this review, we summarize the epigenetic events, including DNA methylation, histone modification, and microRNAs, that result from oxidative stress following experimental stroke in animal and cell models, and the ways in which epigenetic changes and their crosstalk influence the redox state in neurons, glia, and vascular endothelial cells, helping us to understand the foregone and vicious epigenetic regulation of oxidative stress in the vascular neural network following stroke.

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    The Role of Oxidative Stress in Etiopathogenesis of Chemotherapy Induced Cognitive Impairment (CICI)-“Chemobrain”
    Gaman Amelia Maria, Uzoni Adriana, Popa-Wagner Aurel, Andrei Anghel, Petcu Eugen-Bogdan
    Aging and disease. 2016, 7 (3): 307-317.   DOI: 10.14336/AD.2015.1022
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    Chemobrain or chemotherapy induced cognitive impairment (CICI) represents a new clinical syndrome characterised by memory, learning and motor function impairment. As numerous patients with cancer are long-term survivors, CICI represent a significant factor which may interfere with their quality of life. However, this entity CICI must be distinguished from other cognitive syndromes and addressed accordingly. At the present time, experimental and clinical research suggests that CICI could be induced by numerous factors including oxidative stress. This type of CNS injury has been previously described in cancer patients treated with common anti-neoplastic drugs such as doxorubicine, carmustine, methotrexate and cyclophosphamide. It seems that all these pharmacological factors promote neuronal death through a final common pathway represented by TNF alpha (tumour necrosis factor). However, as cancer in general is diagnosed more commonly in the aging population, the elderly oncological patient must be treated with great care since aging per se is also impacted by oxidative stress and potentiually by TNF alpha deleterious action on brain parenchyma. In this context, some patients may develop cognitive dysfunction well before the appearance of CICI. In addition, chemotherapy may worsen their cognitive function. Therefore, at the present time, there is an acute need for development of effective therapeutic methods to prevent CICI as well as new methods of early CICI diagnosis.

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Kunlin Jin, M.D., Ph.D., Professor
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David A. Greenberg, M.D., Ph.D., Professor
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