-
[show abstract]
[hide abstract]
ABSTRACT: Phase 3 trials estimate the effectiveness of an intervention to prevent, delay the onset of, or treat sarcopenia. Participants should have sarcopenia or present a sarcopenia risk profile. Control group should be characterized by the best standard of clinical care. This article further develops issues on sarcopenia definition, target population, primary and secondary end points, duration of the trials, muscle mass assessment, strength and physical performance assessment, and control of possible confounders. The challenges to conduct phase 3 trials in the elderly should not offset the opportunities for the development of new strategies to counteract sarcopenia and prevent late-life disability.
Clinics in Geriatric Medicine 08/2011; 27(3):471-82. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Clinical measures continue to be used as primary endpoints for disease-modifying trials for Alzheimer's disease (AD). Currently, two co-primary endpoints must be specified, which measure cognitive and functional impairments. Generally, the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is one of the co-primary endpoints, but high variability in this measure results in large sample sizes. We evaluated the psychometric properties of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) to assess its suitability as a single primary endpoint as an alternative to the traditional co-primary approach.
Internal consistency, structural and convergent validity, and 2-year internal and external responsiveness of the CDR-SB were assessed in 667 very mild to moderate (global Clinical Dementia Rating, 0.5-2) AD patients from the REAL.FR (Réseau sur la Maladie d'Alzheimer Français) study.
The CDR-SB showed good internal consistency (Cronbach's alpha = 0.88), and acceptable structural (separate "cognitive" and "functional" factors) and convergent validity. Variability in mean changes over time was low, leading to excellent internal responsiveness (effect size = 1.2; standardized response mean = 1.17 at 2 years) and smaller sample sizes as compared with the ADAS-Cog. External responsiveness was acceptable when compared with "clinically meaningful" changes on the Activities of Daily Living scale but only borderline acceptable when compared with the ADAS-Cog and Instrumental Activities of Daily Living. Levels of missing data and floor/ceiling effects were low.
The CDR-SB measures cognitive and functional impairment simultaneously, and has excellent 2-year internal responsiveness. This makes it a promising candidate as a sole primary endpoint for AD trials, although more work is required to determine the clinical relevance of CDR-SB changes, and its usefulness as an endpoint at other disease stages.
Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2011; 7(6):602-610.e2. · 5.90 Impact Factor
-
John E Morley,
Angela Marie Abbatecola,
Josep M Argiles,
Vickie Baracos,
Juergen Bauer,
Shalender Bhasin,
Tommy Cederholm,
Andrew J Stewart Coats,
Steven R Cummings,
William J Evans, [......],
Filippo Rossi-Fanelli,
Giuseppe M C Rosano,
Ronenn Roubenoff,
Morris Schambelan,
Gerald H Sokol,
Thomas W Storer, Bruno Vellas,
Stephan von Haehling,
Shing-Shing Yeh,
Stefan D Anker
[show abstract]
[hide abstract]
ABSTRACT: A consensus conference convened by the Society of Sarcopenia, Cachexia and Wasting Disorders has concluded that "Sarcopenia, ie, reduced muscle mass, with limited mobility" should be considered an important clinical entity and that most older persons should be screened for this condition. "Sarcopenia with limited mobility" is defined as a person with muscle loss whose walking speed is equal to or less than 1 m/s or who walks less than 400 m during a 6-minute walk, and who has a lean appendicular mass corrected for height squared of 2 standard deviations or more below the mean of healthy persons between 20 and 30 years of age of the same ethnic group. The limitation in mobility should not clearly be a result of otherwise defined specific diseases of muscle, peripheral vascular disease with intermittent claudication, central and peripheral nervous system disorders, or cachexia. Clinically significant interventions are defined as an increase in the 6-minute walk of at least 50 meters or an increase of walking speed of at least 0.1 m/s.
Journal of the American Medical Directors Association 07/2011; 12(6):403-9. · 4.64 Impact Factor
-
Bruno Vellas,
Alain Pesce,
Philippe H Robert,
Paul S Aisen,
Sonia Ancoli-Israel,
Sandrine Andrieu,
Jesse Cedarbaum,
Bruno Dubois,
Eric Siemers,
Jean-Paul Spire,
Michael W Weiner,
Thomas S May
[show abstract]
[hide abstract]
ABSTRACT: The recruitment and retention of patients are among the greatest challenges currently being faced by researchers who conduct Alzheimer's disease (AD) clinical trials. To discuss these challenges and other major issues associated with clinical research in AD, an international workshop was organized by the Association Monégasque pour la recherche sur la Maladie d'Alzheimer at Monte Carlo, Monaco, in February 2010, with the participation of leading research experts in the field of Alzheimer's. Key topics discussed were as follows: (1) the selection, recruitment, and retention of clinical trial subjects; (2) international co-operation among researchers; and (3) patient rights and informed consent for participants in clinical trials. This article highlights some of the challenges faced by investigators when conducting clinical trials in AD, and it also offers some recommendations aimed at overcoming these challenges.
Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2011; 7(4):e109-17. · 5.90 Impact Factor
-
Eric Westman,
Andrew Simmons,
J-Sebastian Muehlboeck,
Patrizia Mecocci, Bruno Vellas,
Magda Tsolaki,
Iwona Kłoszewska,
Hilkka Soininen,
Michael W Weiner,
Simon Lovestone,
Christian Spenger,
Lars-Olof Wahlund
[show abstract]
[hide abstract]
ABSTRACT: The European Union AddNeuroMed program and the US-based Alzheimer Disease Neuroimaging Initiative (ADNI) are two large multi-center initiatives designed to collect and validate biomarker data for Alzheimer's disease (AD). Both initiatives use the same MRI data acquisition scheme. The current study aims to compare and combine magnetic resonance imaging (MRI) data from the two study cohorts using an automated image analysis pipeline and a multivariate data analysis approach. We hypothesized that the two cohorts would show similar patterns of atrophy, despite demographic differences and could therefore be combined. MRI scans were analyzed from a total of 1074 subjects (AD=295, MCI=444 and controls=335) using Freesurfer, an automated segmentation scheme which generates regional volume and regional cortical thickness measures which were subsequently used for multivariate analysis (orthogonal partial least squares to latent structures (OPLS)). OPLS models were created for the individual cohorts and for the combined cohort to discriminate between AD patients and controls. The ADNI cohort was used as a replication dataset to validate the model created for the AddNeuroMed cohort and vice versa. The combined cohort model was used to predict conversion to AD at baseline of MCI subjects at 1 year follow-up. The AddNeuroMed, the ADNI and the combined cohort showed similar patterns of atrophy and the predictive power was similar (between 80 and 90%). The combined model also showed potential in predicting conversion from MCI to AD, resulting in 71% of the MCI converters (MCI-c) from both cohorts classified as AD-like and 60% of the stable MCI subjects (MCI-s) classified as control-like. This demonstrates that the methods used are robust and that large data sets can be combined if MRI imaging protocols are carefully aligned.
NeuroImage 07/2011; 58(3):818-28. · 5.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The Mini-Nutritional Assessment (MNA) is recommended to assess malnutrition in older people. However, its implementation is challenging in large elderly population, nursing home, or community or large clinical research programs. The Simplified Nutritional Appetite Questionnaire (SNAQ), a self-assessment nutritional screening tool that predicts weight loss, could be used to screen older people at risk of malnutrition or malnourishment. Our objective was to assess whether the SNAQ is related to the MNA and can screen older people at risk of malnutrition or malnourishment.
Cross-sectional study conducted of 175 persons aged 65 or older who were community dwelling, hospitalized, and nursing home residents.
The SNAQ and the MNA score were performed. Correlation between the scores was studied. The most discriminating SNAQ value, which separated the participant at risk of malnutrition or malnourishment from the participant with a normal nutrition status (defined by MNA), was calculated.
The SNAQ and the MNA score were significantly correlated (Spearman test r = 0.48, P < .001). The distribution of the population using the SNAQ or the MNA was significantly different (MacNemar P < .01). The area under the receiver operator characteristic curve, which assesses the ability of the SNAQ score to predict an abnormal MNA score, was 0.767 (95% confidence interval, 0.69-0.85). An SNAQ score under 14 was the best clinical indicator of older people at risk of malnutrition or malnourishment (sensitivity = 71%, specificity = 74%). Using this cut-off, 26.8% of the population (n = 47) were misclassified. Most of them (n = 33; 18.8%) had an abnormal SNAQ with a normal MNA.
The SNAQ is a poor screening tool to predict older people with an abnormal MNA score. However, an abnormal SNAQ might identify those who will lose weight earlier than will the MNA.
Journal of the American Medical Directors Association 06/2011; 13(1):31-4. · 4.64 Impact Factor
-
Michael Ewers,
Susanne Schmitz,
Oskar Hansson,
Cathal Walsh,
Annette Fitzpatrick,
David Bennett,
Lennart Minthon,
John Q Trojanowski,
Leslie M Shaw,
Yetunde O Faluyi, Bruno Vellas,
Bruno Dubois,
Kaj Blennow,
Katharina Buerger,
Stefan J Teipel,
Michael Weiner,
Harald Hampel
[show abstract]
[hide abstract]
ABSTRACT: Weight changes are common in aging and Alzheimer's disease (AD) and postmortem findings suggest a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF)-based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Aβ(1-42)), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF-). Results showed that BMI was significantly lower in the CSF+ when compared with the CSF- group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or apolipoprotein E (ApoE) genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and nondemented elderly subjects.
Neurobiology of aging 06/2011; 33(8):1599-608. · 5.94 Impact Factor
-
Roger A Fielding, Bruno Vellas,
William J Evans,
Shalender Bhasin,
John E Morley,
Anne B Newman,
Gabor Abellan van Kan,
Sandrine Andrieu,
Juergen Bauer,
Denis Breuille, [......],
Aimo Kannt,
Florence Keime Guibert,
Graziano Onder,
Dimitris Papanicolaou,
Yves Rolland,
Daniel Rooks,
Cornel Sieber,
Elisabeth Souhami,
Sjors Verlaan,
Mauro Zamboni
[show abstract]
[hide abstract]
ABSTRACT: Sarcopenia, the age-associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability, and health care planning. A group of geriatricians and scientists from academia and industry met in Rome, Italy, on November 18, 2009, to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia may be a component of sarcopenia, the 2 conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1 m/s(-1). Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m·s(-1) and an objectively measured low muscle mass (eg, appendicular mass relative to ht(2) that is ≤ 7.23 kg/m(2) in men and ≤ 5.67 kg/m(2) in women). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization, and death.
Journal of the American Medical Directors Association 05/2011; 12(4):249-56. · 4.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Sarcopenia is the key feature of frailty in older people and a major determinant of adverse health outcomes such as functional limitations and disability. Resistance training and adequate protein and energy intake are the key strategies for the management of sarcopenia. Management of weight loss and resistance training are the most relevant protective countermeasures to slow down the decline of muscle mass and muscle strength. The quality of amino acids in the diet is an important factor for stimulating protein synthesis. Vitamin D deficiency should be treated, and new pharmacologic approaches for sarcopenia are currently assessed.
The Medical clinics of North America 05/2011; 95(3):427-38, ix. · 2.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: antipsychotics are widely used in assisted living (AL facilities). Even more, the prescription of these drugs is gradually increasing since the availability of second-generation atypical antipsychotics. More knowledge is needed on prescription reasons to understand this increasing prevalence.
cross-sectional analysis of 4,367 residents. Data were obtained from medical records assessed by geriatricians from the AL facility. A multiple logistic regression model (backward stepwise) was used to assess the independent associated factors with antipsychotic use.
antipsychotic prescription was found in 1,203 (27.5%) of 4,367 residents. The independent associated factors with the use of antipsychotics were the presence of a psychiatric disorder [odds ratio, OR = 5.30 (4.42-6.35)], the age under 80 years [OR = 2.08 (1.62-2.68)], admission from another institution [OR = 1.49 (1.12-1.98)], treated dementia [OR = 1.84 (1.47-2.30)], the presence of neuropsychiatric symptoms (NPS): verbal outbursts [OR = 2.58 (1.96-3.39)], threatening behaviours or physical violence [OR = 2.13 (1.71-2.65)], and aimless wandering [OR = 1.55 (1.17-2.04)], the presence of cardiovascular disease [OR = 0.79 (0.65-0.96)] and the presence of cerebrovascular disease [OR = 0.77 (0.64-0.92)].
the study found that more than a quarter of the residents received antipsychotics. This study also highlighted the independent associated factors with antipsychotic prescription showing 'off-label' prescriptions in conditions such as dementia and certain NPS. The study findings suggest that improvements in the management of dementia and NPS in AL facilities are needed. Non-pharmacological alternatives should be enhanced and further developed viewing the high prevalence of antipsychotic prescription.
Age and Ageing 03/2011; 40(3):368-75. · 3.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A major health policy objective is to encourage and sustain informal caregiving networks for people with Alzheimer's disease (AD). This goal can be reached by providing financial assistance to patients facing difficulties in the accomplishment of activities of daily living, in order to encourage utilization of professional service and therefore alleviate informal caregiver burden. The main issue is to understand if and how financial assistance is correlated with the distribution between informal and professional care. We used a cross-sectional sample of 1131 French elderly patients (≥65) with mild to moderate AD. Informal and professional service resource use was measured in hours per month using a validated instrument, the Resource Use in Dementia questionnaire. Our results confirmed the utter dominance of informal care, which represented more than 80% of total care even among patients receiving public financial support. However financial support receipt was associated with differences in care utilization: higher use of total non-medical care (formal and informal) and lower proportion of informal care in total non-medical care. Our results suggested the presence of a threshold effect that would influence non-medical care demand decisions. Even if on average the use of informal care in total was 13.3% lower among patients receiving public financial support, informal care use represented more than 80% of total non-medical care use. Providing robust evidence of these associations is crucial to further identify the right dosage between professional service demand and informal care utilization that could be associated with a lower burden and therefore a lower probability of institutionalization.
Social Science [?] Medicine 03/2011; 72(8):1310-6. · 2.70 Impact Factor
-
Debbie Tolson,
Yves Rolland,
Sandrine Andrieu,
Jean-Pierre Aquino,
John Beard,
Athanase Benetos,
Gilles Berrut,
Laura Coll-Planas,
Birong Dong,
Françoise Forette,
Alain Franco,
Simone Franzoni,
Antoni Salvà,
Daniel Swagerty,
Marco Trabucchi, Bruno Vellas,
Ladislav Volicer,
John E Morley
[show abstract]
[hide abstract]
ABSTRACT: A workshop charged with identifying the main clinical concerns and quality of care issues within nursing homes was convened by the International Association of Gerontology and Geriatrics, with input from the World Health Organization. The workshop met in Toulouse, France, during June 2010. Drawing on the latest evidence and mindful of the international development agenda and specific regional challenges, consensus was sought on priority actions and future research. The impetus for this work was the known variation in the quality of nursing home care experiences of older people around the world. The resulting Task Force recommendations include instigation of sustainable strategies designed to enhance confidence among older people and their relatives that the care provided within nursing homes is safe, mindful of their preferences, clinically appropriate, and delivered with respect and compassion by appropriately prepared expert doctors, registered nurses, administrators, and other staff. The proposals extend across 4 domains (Reputational Enhancement and Leadership, Clinical Essentials and Care Quality Indicators, Practitioner Education, and Research) that, in concert, will enhance the reputation and status of nursing home careers among practitioners, promote effective evidence-informed quality improvements, and develop practice leadership and research capabilities.
Journal of the American Medical Directors Association 03/2011; 12(3):184-9. · 4.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: It has been shown that, during several years preceding the diagnosis of Alzheimer's disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer's disease or dementia. During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer's disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer's disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer's disease.
CNS Drugs 03/2011; 25(3):213-26. · 4.80 Impact Factor
-
Zaven S Khachaturian,
Ronald C Petersen,
Peter J Snyder,
Ara S Khachaturian,
Paul Aisen,
Mony de Leon,
Barry D Greenberg,
Walter Kukull,
Paul Maruff,
Reisa A Sperling,
Yaakov Stern,
Jacques Touchon, Bruno Vellas,
Sandrine Andrieu,
Michael W Weiner,
Maria C Carrillo,
Lisa J Bain
[show abstract]
[hide abstract]
ABSTRACT: The fourth Leon Thal Symposium (LTS2010) was convened in Toulouse, France, on November 3, 2010. This symposium reviewed design parameters that are necessary to develop comprehensive national databases on healthy aging. Such datasets offer the potential to serve as the foundation for a systems-approach to solve the dual public health problems of: (1) early detection of people who are at elevated risk for Alzheimer's disease, and (2) the development of interventions to delay onset of, or prevent, late-life dementia. The symposium considered three interrelated components of a National Database for Longitudinal Studies on Healthy Aging as follows: (a) a registry of healthy aging adults; (b) refined computer-based assessments for data gathering, including assessments of behavioral/memory changes associated with aging that are appropriate for broad use in nonexpert settings; and (c) high performance computing/supercomputer-based approaches for health data modeling and mining.
Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2011; 7(2):127-32. · 5.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Therapies to treat osteoporosis remain underutilized and minimally evaluated in frail elderly patients. Our study determined and compared the risk of vertebral fractures in frail, intermediate and robust older patients being treated with strontium ranelate vs. placebo.
Data were obtained from the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of Peripheral Osteoporosis) studies which randomized participants to receive either strontium ranelate or placebo over 3 years. Frail, intermediate and robust patients were identified using adapted Fried's criteria. Analyses were performed according to the intention-to-treat principle utilizing 1- and 3-year study follow-up data.
2346 robust, 2472 intermediate and 264 frail women were identified. At 3 years, the risk for vertebral fractures was reduced by 30% (Relative Risk [RR], 0.70; 95% confidence interval [CI], 0.57-0.86) in the robust, by 45% (RR, 0.55; 95%CI, 0.46-0.67) in the intermediate and by 58% (RR, 0.42; 95%CI, 0.24-0.74) in the frail patients compared to those assigned to placebo (p<0.01 for all three groups; p=0.11 for trend). Risk of vertebral fracture was significantly reduced within 1 year in all three groups. Numbers of subjects needed to be treated to prevent one new vertebral fracture over 3 years were 13, 9 and 5 in the robust, intermediate and frail groups, respectively. Adverse event profiles and medication compliance were similar across the 3 groups.
The imperative to treat osteoporosis appears to be greatest in frail patients since similar relative risk reductions would avert more fractures in frail than in non-frail elderly patients.
Bone 02/2011; 48(2):332-8. · 4.02 Impact Factor
-
Eric Westman,
Andrew Simmons,
Yi Zhang,
J-Sebastian Muehlboeck,
Catherine Tunnard,
Yawu Liu,
Louis Collins,
Alan Evans,
Patrizia Mecocci, Bruno Vellas,
Magda Tsolaki,
Iwona Kłoszewska,
Hilkka Soininen,
Simon Lovestone,
Christian Spenger,
Lars-Olof Wahlund
[show abstract]
[hide abstract]
ABSTRACT: We have used multivariate data analysis, more specifically orthogonal partial least squares to latent structures (OPLS) analysis, to discriminate between Alzheimer's disease (AD), mild cognitive impairment (MCI) and elderly control subjects combining both regional and global magnetic resonance imaging (MRI) volumetric measures. In this study, 117 AD patients, 122 MCI patients and 112 control subjects (from the AddNeuroMed study) were included. High-resolution sagittal 3D MP-RAGE datasets were acquired from each subject. Automated regional segmentation and manual outlining of the hippocampus were performed for each image. Altogether this yielded volumes of 24 different anatomically defined structures which were used for OPLS analysis. 17 randomly selected AD patients, 12 randomly selected control subjects and the 22 MCI subjects who converted to AD at 1-year follow up were excluded from the initial OPLS analysis to provide a small external test set for model validation. Comparing AD with controls we found a sensitivity of 87% and a specificity of 90% using hippocampal measures alone. Combining both global and regional measures resulted in a sensitivity of 90% and a specificity of 94%. This increase in sensitivity and specificity resulted in an increase of the positive likelihood ratio from 9 to 15. From the external test set, the model predicted 82% of the AD patients and 83% of the control subjects correctly. Finally, 73% of the MCI subjects which converted to AD at 1 year follow-up were shown to resemble AD patients more closely than controls. This method shows potential for distinguishing between different patient groups. Combining the different MRI measures together resulted in a significantly better classification than using them separately. OPLS also shows potential for predicting conversion from MCI to AD.
NeuroImage 01/2011; 54(2):1178-87. · 5.89 Impact Factor
-
Eric Westman,
Andrew Simmons,
Sebastian Muehlboeck,
Patrizia Mecocci, Bruno Vellas,
Magda Tsolaki,
Iwona Kloszewska,
Hilkka Soininen,
Michael W. Weiner,
Simon Lovestone,
Christian Spenger,
Lars-Olof Wahlund
NeuroImage. 01/2011; 58:818-828.
-
Michelle K Lupton,
Petroula Proitsi,
Makrina Danillidou,
Magda Tsolaki,
Gillian Hamilton,
Richard Wroe,
Megan Pritchard,
Kathryn Lord,
Belinda M Martin,
Iwona Kloszewska,
Hilkka Soininen,
Patrizia Mecocci, Bruno Vellas,
Denise Harold,
Paul Hollingworth,
Simon Lovestone,
John F Powell
[show abstract]
[hide abstract]
ABSTRACT: Nicastrin is an obligatory component of the γ-secretase; the enzyme complex that leads to the production of Aβ fragments critically central to the pathogenesis of Alzheimer's disease (AD). Analyses of the effects of common variation in this gene on risk for late onset AD have been inconclusive. We investigated the effect of rare variation in the coding regions of the Nicastrin gene in a cohort of AD patients and matched controls using an innovative pooling approach and next generation sequencing. Five SNPs were identified and validated by individual genotyping from 311 cases and 360 controls. Association analysis identified a non-synonymous rare SNP (N417Y) with a statistically higher frequency in cases compared to controls in the Greek population (OR 3.994, CI 1.105-14.439, p = 0.035). This finding warrants further investigation in a larger cohort and adds weight to the hypothesis that rare variation explains some of genetic heritability still to be identified in Alzheimer's disease.
PLoS ONE 01/2011; 6(2):e17298. · 4.09 Impact Factor
-
Madhav Thambisetty,
Andrew Simmons,
Abdul Hye,
James Campbell,
Eric Westman,
Yi Zhang,
Lars-Olof Wahlund,
Anna Kinsey,
Mirsada Causevic,
Richard Killick,
Iwona Kloszewska,
Patrizia Mecocci,
Hilkka Soininen,
Magda Tsolaki, Bruno Vellas,
Christian Spenger,
Simon Lovestone
[show abstract]
[hide abstract]
ABSTRACT: Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods-quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, γ-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis.
PLoS ONE 01/2011; 6(12):e28527. · 4.09 Impact Factor
-
Simon J Furney,
Deborah Kronenberg,
Andrew Simmons,
Andreas Güntert,
Richard J Dobson,
Petroula Proitsi,
Lars Olof Wahlund,
Iwona Kloszewska,
Patrizia Mecocci,
Hilkka Soininen,
Magda Tsolaki, Bruno Vellas,
Christian Spenger,
Simon Lovestone
[show abstract]
[hide abstract]
ABSTRACT: Progression of people presenting with Mild Cognitive Impairment (MCI) to dementia is not certain and it is not possible for clinicians to predict which people are most likely to convert. The inability of clinicians to predict progression limits the use of MCI as a syndrome for treatment in prevention trials and, as more people present with this syndrome in memory clinics, and as earlier diagnosis is a major goal of health services, this presents an important clinical problem. Some data suggest that CSF biomarkers and functional imaging using PET might act as markers to facilitate prediction of conversion. However, both techniques are costly and not universally available. The objective of our study was to investigate the potential added benefit of combining biomarkers that are more easily obtained in routine clinical practice to predict conversion from MCI to Alzheimer's disease. To explore this we combined automated regional analysis of structural MRI with analysis of plasma cytokines and chemokines and compared these to measures of APOE genotype and clinical assessment to assess which best predict progression. In a total of 205 people with MCI, 77 of whom subsequently converted to Alzheimer's disease, we find biochemical markers of inflammation to be better predictors of conversion than APOE genotype or clinical measures (Area under the curve (AUC) 0.65, 0.62, 0.59 respectively). In a subset of subjects who also had MRI scans the combination of serum markers of inflammation and MRI automated imaging analysis provided the best predictor of conversion (AUC 0.78). These results show that the combination of imaging and cytokine biomarkers provides an improvement in prediction of MCI to AD conversion compared to either datatype alone, APOE genotype or clinical data and an accuracy of prediction that would have clinical utility.
Journal of Alzheimer's disease: JAD 01/2011; 26 Suppl 3:395-405. · 3.74 Impact Factor
