FUS knockdown induces increased cell death in HeLa and SH-SY5Y

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Poster Presentations P1 EFFECT OF SWITCHING TREATMENT WITH GALANTAMINE IN PATIENTS WITH MILD-TOMODERATE ALZHEIMER’S DISEASE

Taeyoung Hwang, St. Andrew Hospital, Icheon, Republic of Korea. Contact e-mail: [email protected] Background: The purpose of this study is to investigate the effect of switching treatment with galantamine in patients with Alzheimer’s disease (AD) who showed a lack of efficacy to other cholinesterase inhibitor (ChEI). Methods: Seventy patients with probable AD of mild-to-moderate severity were recruited for this 52-week, single-blind, prospective study. A total of 66 patients satisfied the criteria for the Intent-to-treat (ITT) analysis, and were classified into two groups, the drug-naı¨ve group (n ¼ 42) and the switched group (n ¼ 24). The switched group targeted patients who had shown a lack of efficacy after at least 6 months of treatment with donepezil. The primary outcome measures were the response rate after 26 weeks of treatment and the change on a Korean version of the Alzheimer’s Disease Assessment Scale-cognitive subscale (K-ADAS-cog). Secondary outcomes were measured using a Korean version of the Mini-Mental State Examination (K-MMSE), Seoul-Activities of Daily Living (S-ADL), Seoul-Instrumental Activities of Daily Living (S-IADL) and Korean version of the Neuropsychiatric Inventory (K-NPI). Results: There were no significant between-group differences in the response rate to galantamine (71.4% for the naı¨ve group vs. 58.3% for the switched group; c2 ¼ 1.178, df ¼ 1, p ¼ 0.277) and the adjusted change on the cognitive scales (K-ADAScog, K-MMSE) and non-cognitive scales (S-IADL, S-ADL, and K-NPI) at each point of evaluation. Stratification analysis by severity showed that if the duration of illness is constant, the probability of response is significantly higher in the naı¨ve group than in the switched group only at moderate severity (c2 ¼ 4.09, df ¼ 1, p-value ¼ 0.043; multiple logistic regression for the adjustment of between-group difference in duration of illness), but not at mild severity. Conclusions: The findings of this study suggest that previous exposure to other ChEI does not preclude the effect of switching treatment with galantamine on cognition, function, and behavior in the treatment of patients with mild-to-moderate AD, while switching treatment with galantamine may be more effective in the earlier stages of AD. P1-461

IMPROVEMENT OF WORKING MEMORY AFTER BILATERAL PREFRONTAL TRANSCRANIAL DC STIMULATION IN HEALTHY ELDERLY

Myoung-Hwan Ko1,2, Min-Ho Seo1, Jeong-Hwan Seo1, Yun-Hee Kim3, Chonbuk National University Medical School, Jeonju, Republic of Korea; 2 Medical Device Clinical Trial Center, Chonbuk National University Hospital, Jeonju, Republic of Korea; 3Sungkyunkwan University School of Medicine & Samsung Medical Center, Seoul, Republic of Korea. Contact e-mail: [email protected] 1

Background: Noninvasive transcranial direct current stimulation (tDCS) can modulate the cortical excitability and has been applied for improvement of brain functions. We investigated the effects of bilateral prefrontal tDCS in healthy elderly by means of verbal and visual working memory tasks. Methods: Fifteen healthy elderly (9 males, 6 females, and mean age 70.7) were enrolled in this study. A sham controlled, double-blind and crossover study was conducted. Subjects underwent three experimental sessions, 1) sham, 2) anodal DC over left prefrontal (F3), and 3) dual anodal DC over bilateral prefrontal (F3&F4 in 10-20 EEG system) cortices. DC was delivered for 20 minute at 2 mA with 25 cm2 saline-soaked sponge electrodes. Cathode electrode was applied on left arm. Before and after tDCS, subjects were performed 2-back verbal working memory and visual memory tasks. The improvement rate of the accuracy and the reaction time after three sessions were analyzed using ANOVA and post-hoc t-test. Results: In 2-back verbal working memory task, the improvement rate of accuracy was significantly higher after bilateral prefrontal tDCS (8.2%) than sham (-0.2) (P ¼ 0.04), the improvement rate of reaction time was also significantly higher after bilteral prefrontal tDCS (7.9%) than sham (-2.1%) (P ¼ 0.01). In visual working memory task, the improvement rate of reaction time was signifi-

cantly higher after single left prefrontal tDCS (13.6%) than sham (-0.1%) (P ¼ 0.01) and bilateral prefrontal tDCS (13.7%) than sham (P ¼ 0.02). Conclusions: The results showed beneficial effects of noninvasive transcranial anodal DC stimulation on cognitive function in healthy elderly. Especially, the bilateral prefrontal anodal tDCS can be more effective method to improve working memory. We suggest that tDC-induced changes in neural excitability could be provide an adjuvant treatment tool for facilitating cognitive function in elderly population. P1-462

MEMANTINE AND PREVENTION OF WORSENING IN FUNCTIONAL COMMUNICATION: POST HOC ANALYSIS OF A RANDOMIZED, PLACEBOCONTROLLED TRIAL IN PATIENTS WITH MODERATE ALZHEIMER’S DISEASE

Robert K. Hofbauer1, Michael Tocco1, Suzanne Hendrix2, Stephen M. Graham1, James L. Perhach1, 1Forest Research Institute, Jersey City, NJ, USA; 2Pentara Corporation, Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: In patients with Alzheimer’s disease (AD), a declining ability to communicate has been associated with increased caregiver stress. In a previously reported, randomized trial in moderate AD (NCT00469456), memantine was superior to placebo at improving functional communication, as recognized by caregivers. Here we focus on patients from that trial who experienced a worsening on two measures of functional communication: the primary study endpoint, an assessment of patients using the Functional Linguistic Communication Inventory (FLCI), and the secondary study endpoint, an assessment of caregivers using the combined Social Communication and Communication of Basic Needs subscales of the American Speech-Language-Hearing Association - Functional Assessment of Communication Skills of Adults scale (ASHA-FACS). Methods: Native English-speaking outpatients with AD (MMSE range: 10-19) participated in a 12-week, international, double-blind, randomized study of memantine (20 mg/day; ITT n ¼ 133) versus placebo (ITT n ¼ 124). Concurrent cholinesterase inhibitor treatment, stable throughout the study, was permitted but not required. In this post hoc analysis (LOCF), we selected patients whose changes on the FLCI or the ASHA-FACS subscales indicated any worsening (<0, both measures), greater-than-mild worsening (decline of more than 0.5 standard deviations: FLCI, <-3; ASHA-FACS, <-10), or greater-than-moderate worsening (decline of more than 1.0 standard deviation: FLCI, <-6; ASHA-FACS, <-20). We then used Generalized Estimating Equations to compare treatment groups in terms of proportions of patients who experienced each degree of worsening at endpoint and overall (i.e., throughout the trial). Results: On the FLCI, no significant difference was observed between memantine and placebo in the proportion of patients who experienced any decline (endpoint and overall); however, a significantly higher percentage of patients in the placebo group experienced greater-than-mild worsening at endpoint (P ¼ 0.032) and overall (P ¼ 0.013) and greater-than-moderate worsening at endpoint (P ¼ 0.039) but not overall (P ¼ 0.081). On the ASHA-FACS, significantly more caregivers of patients taking placebo relative to memantine reported any worsening overall (P ¼ 0.013) but not at endpoint (P ¼ 0.079); significantly greater-than-mild worsening at endpoint (P ¼ 0.012) and overall (P ¼ 0.018), and significantly greater-than-moderate worsening at endpoint (P ¼ 0.011), though not overall (P ¼ 0.133). Conclusions: Memantine treatment of patients with moderate AD may be associated with a prevention of worsening in functional communication.

P1-463

FUS KNOCKDOWN INDUCES INCREASED CELL DEATH IN HELA AND SH-SY5Y

Amadeus Gladbach1, Yazi Ke1, Janet van Eersel1, Jurgen Gotz1, Nikolas Haass2, Lars M. Ittner1, 1The University of Sydney, Camperdown, NSW, Australia; 2Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW, Australia. Contact e-mail: [email protected] Background: Frontotemporal lobar degeneration (FTLD) is the second most common neurodegenerative disorder at an age under 65. The identification of different proteinous deposits has led to a sub-classification; in

Poster Presentations P2 FTLD-TAU, hyperphosphorylated forms of tau are the major constituent of lesions, while in FTLD-TDP the TAR-DNA-binding Protein 43 (TDP-43) deposits, and in FTLD-FUS it is the protein fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS) or heterogenous ribonuclear protein (hnRNP)) that forms inclusions. Similarly, FUS deposits are found in amyotrophic lateral sclerosis (ALS), the most common form of motor neuron degeneration. A pathogenic role of FUS in neurodegeneration is further supported by the identification of mutations in FUS in ALS. As a transcription factor, FUS is mainly localized to the nucleus, where it interacts with other transcription factors and regulates RNA-expression. Furthermore, FUS contributes to the regulation of actin cytoskeleton in the cytoplasm. Methods: Here we use lentiviral MISSIONTM siRNA driven knock-down to study the effects of FUS reduction in SH-SY5Y neuroblastoma and HeLa cervical cancer cells. Cells were analyzed by fluorescenceactivated-cell-sorting (FACS), Western blotting and immunocytochemistry (ICC). Results: Levels of knock-down of FUS were determined by Western Blots, FACS and ICC. FUS levels were reduced by 30 to 90% in different stably selected lines. Reduction of FUS resulted in increased numbers of apoptotic cell death as determined by Annexin-V and Sytox labeling. In addition, FUS reduction is associated with increased amount of cleaved caspase 3. Conclusions: Loss of FUS is associated with an increase in apoptotic cell death in both SH-SY5Y and HeLa-cells. Hence in disease, loss-of-physiological-function of FUS associated with its aggregation in the cytoplasm may contribute to neurodegeneration in FTLD and ALS. MONDAY, JULY 12, 2010 POSTER PRESENTATIONS P2 P2-001

CAREGIVER BURDEN IN ALZHEIMER’S DISEASE

Diane Ito1, Jonathan Stokes2, Elizabeth Piault-Louis2, Patrick Bonnet1, 1 Baxter Healthcare Corporation, Westlake Village, CA, USA; 2Mapi Values, Boston, MA, USA. Contact e-mail: [email protected] Background: The majority of patients with AD live outside institutions and the burden associated with caring for a patient with dementia often falls upon informal caregivers, such as a spouse or other family member. The demanding nature of AD care can take a significant toll on the caregiver, resulting in diminished physical or mental health. Methods: Qualitative focus group discussions were conducted with 21 caregivers in three geographically diverse US cities to elicit the impacts of care giving for AD patients. IRB approval was granted for this qualitative research. Results: Nearly all of the AD caregivers (90%) were caring for a relative with AD and spent an average of 35.3 hours per week in care giving duties. Caregivers of AD patients referred to their lack of experience with handling a degenerative and debilitating condition. Caregivers expressed feelings of frustration (n ¼ 11), isolation (n ¼ 7), and guilt (n ¼ 5) as aspects of the general strain associated with caring for a patient with AD. Social limitations (n ¼ 17), as well as difficulties with sleep (n ¼ 9) and maintenance of well-being (n ¼ 5) were also exhibited by caregivers. Appraisals of burden qualitatively differed according to the caregiver’s relationship with the patient (i.e., spouse or child) but also their working or marital status. The concept of caregiver burden was discussed as a responsibility or an obligation to the patient where the caregiver would often put the needs of the patient above their own. Conclusions: These results highlight the numerous deleterious impacts on the caregiver’s HRQL. The growth of the geriatric population calls for education tools and evaluative assessment of caregivers’ well-being to ensure the quality of support that patients receive and to identify the origins and management of caregiver burden. P2-002

A DESCRIPTION OF ADULT CHILD AND SPOUSE CAREGIVERS OF PERSONS WITH ALZHEIMER’S DISEASE: REACTIONS TO LOSS

Cynthia M. Steinwedel1,2, Carol H. Ott3, Sarah Morgan2, 1Bradley University, Peoria, IL, USA; 2University of Wisconsin - Milwaukee, Milwaukee, WI, USA; 3Columbia College of Nursing, Milwaukee, WI, USA. Contact e-mail: [email protected]

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Background: The experience of family caregivers of persons with dementia has been described as both stressful and burdensome. Family caregivers are thrust into an ever-deepening, demanding role of caring for a spouse or parent who gradually becomes increasingly distant and yet dependent, unreachable and yet intrusive, lost and yet still present. In recent years authors have described the grief component of the caregiving experience which accompanies the burden and stress. Methods: A mixed method study included narrative thematic analysis of interviews with 50 family caregivers of persons with advanced dementia. Data from adult child caregivers (N ¼ 17) as well as spouse caregivers (N ¼ 33). Quantitative data from Marwit and Meuser Caregiver Grief Inventory - Short Form, Revised Dyadic Adjustment Scale, and Brief COPES were examined to see if they supported the results of thematic qualitative analysis. Results: Although concerns of adult child and spouse caregivers differed, both groups were found to have significant concerns in three thematic areas: grief, burden, and carrying on. Subthemes and differences were also identified between adult children and spouse caregivers. Quantitative data from Marwit and Meuser Caregiver Grief Inventory - Short Form, Revised Dyadic Adjustment Scale, and Brief COPES supported differences in themes found between the adult child and spouse caregivers as revealed by interview thematic analysis. Although both groups scored relatively high on the MMCGI-SF, adult children were found to have higher levels of burden and used active coping methods, while spouse caregivers were more likely to feel intense grief, sadness, and longing. Conclusions: Implications for health care include identification of grief and coping in caregivers; need for supportive care for families; and interventions to cope with feelings of loss, lack of freedom, isolation. P2-003

SLEEP PERCEPTION IN CAREGIVERS OF PEOPLE WITH ALZHEIMER’S DISEASE

Marco Vista1, Barbara Bertocci2, Fiorenza Giganti3, Iole Zilli3, Ines Esposito3, Lucia Picchi4, Monica Mazzoni1, Paola Cavallero3, 1Alzheimer’s Diagnostic Unit, Lucca Hospital, Lucca, Italy; 2Department of Psychology, University of Bologna, Bologna, Italy; 3Dept. of Psychology, University of Florence, Florence, Italy; 4Unit of Neurology, Versilia Hospital, Lido di Camaiore, Italy. Contact e-mail: [email protected] Background: Caregivers of people with Alzheimer’s Disease (cADs) are affected by sleep problems which show remarkable changes during the different phases of the illness. Past literature highlighted how cADs often complain about having problems such as disturbed sleep and poor quality sleep. The decisive factors that contribute to sleep disturbance of cADs seem to be chronic stress, activity of nighttime caregiving, perceived burden, and the gravity of the pathology. Methods: 40 cADs of patients taken in load by the Alzheimer Diagnostic Unit (ADU) of Lucca Hospital for the first time have been assessed by means of Caregiver Burden Inventory, Satisfaction With Life Scale, and a questionnaire on the subjective quality of sleep and its quantitative characteristics perceived by each subject. Collected data have been subjected to descriptive analysis and Kendall’s tau-b correlations. Results: Descriptive statistics analyses shown that only a few subjects suffer from poor quality and insufficient quantity of sleep; nevertheless, correlation analyses highlighted that the burden perceived by the caregivers affects their perception of the quantity and quality of sleep. Besides, some social factors and the quality of their living place turned out to be protective factors as they appear to modulate cADs’ perception and evaluation of sleep. Conclusions: Although sleep disturbance results from our study to be not so frequent, those factors need to be followed up in order to verify their trend during the worsening of the pathology and the increasing of the perceived burden. Those results could be explained by the short time elapsed between the disclosure of the diagnosis to the cADs and the occurred interview. P2-004

DETERMINANTS OF CARE BURDEN OF CAREGIVERS IN PATIENTS WITH DEMENTIA: RELATIOSHIPS WITH COGNITIVE DYSFUNCTION

Jin Yeong Kim1, InWon Chung1, SungMan Chang2, 1DongGuk University International Hospital, Goyang, Republic of Korea; 2Kyungpook National University College of Medicine, Daegu, Republic of Korea. Contact e-mail: [email protected]