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1.  FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer’s disease 
Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer’s disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD.
In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion.
A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510–70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups.
FOXO1 may influence the clinical response to AChEIs in AD patients.
PMCID: PMC4211854  PMID: 25364236
forkhead box O1; acetylcholinesterase inhibitors; response to treatment
2.  Effects of hypercapnia on peripheral vascular reactivity in elderly patients with acute exacerbation of chronic obstructive pulmonary disease 
Blood acid-base imbalance has important effects on vascular reactivity, which can be related to nitric oxide (NO) concentration and increased during hypercapnia. Release of NO seems to be linked to H+ and CO2 concentration and to exacerbation of chronic obstructive pulmonary disease (COPD), a common medical condition in the elderly. Flow-mediated dilation (FMD), a valuable cardiovascular risk indicator, allows assessment of endothelial-dependent vasodilation, which is to a certain extent mediated by NO. We investigated the effects of hypercapnia and acid-base imbalance on endothelial-dependent vasodilation by measurement of FMD in 96 elderly patients with acute exacerbation of COPD. Patients underwent complete arterial blood gas analysis and FMD measurement before (phase 1) and after (phase 2) standard therapy for acute exacerbation of COPD and recovery. Significant differences between phase 1 and phase 2 were observed in the mean values of pH (7.38±0.03 versus 7.40±0.02, P<0.001), pO2 (59.6±4.9 mmHg versus 59.7±3.6 mmHg, P<0.001), pCO2 (59.3±8.63 mmHg versus 46.7±5.82 mmHg, P<0.001), FMD (10.0%±2.8% versus 8.28%±2.01%, P<0.001) and blood flow rate (1.5±0.3 m/s versus 1.5±0.3 m/s, P=0.001). FMD values were positively correlated with pCO2 values (r=0.294, P=0.004) at baseline. A significant correlation was also found between relative changes in FMD and pCO2 levels, passing from phase 1 to phase 2 (r=0.23, P=0.023). Patients with higher baseline endothelium-dependent vasodilation as evaluated by FMD showed greater modification with regard to pCO2 changes (2.6±1.39 versus 1.59±1.4, P=0.012). In conclusion, endothelium-dependent vasodilation as evaluated by FMD was elevated during hypercapnia, and varied significantly according to pCO2 changes in patients with higher baseline levels, suggesting that vascular reactivity in acute COPD exacerbations in the elderly depends on integrity of the vascular endothelium.
PMCID: PMC4043425  PMID: 24904207
hypercapnia; elderly; chronic obstructive pulmonary disease; vascular reactivity; flow-mediated dilation
3.  Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging 
Age  2011;35(2):441-453.
Midlife elevated blood pressure and hypertension contribute to the development of Alzheimer's disease (AD) and overall dementia. We sought to estimate whether angiotensin-converting enzyme inhibitors (ACE-Is) reduced the risk of developing mild cognitive impairment (MCI) in cognitively normal individuals. In the Italian Longitudinal Study on Aging, we evaluated 1,445 cognitively normal individuals treated for hypertension but without congestive heart failure from a population-based sample from eight Italian municipalities with a 3.5-year follow-up. MCI was diagnosed with current clinical criteria. Dementia, AD, and vascular dementia were diagnosed based on DSM-IIIR criteria, NINCDS–ADRDA criteria, and ICD-10 codes. Among 873 hypertension-treated cognitively normal subjects, there was no significant association between continuous exposure to all ACE-Is and risk of incident MCI compared with other antihypertensive drugs [hazard ratio (HR), 0.45, 95% confidence interval (CI), 0.16–1.28]. Captopril exposure alone did not significantly modify the risk of incident MCI (HR, 1.80, 95% CI, 0.39–8.37). However, the enalapril sub-group alone (HR, 0.17, 95% CI, 0.04 –0.84) or combined with the lisinopril sub-group (HR, 0.27, 95% CI, 0.08–0.96), another ACE-I structurally related to enalapril and with similar potency, were associated with a reduced risk of incident MCI. Study duration exposure to ACE-Is as a “class” was not associated with incident MCI in older hypertensive adults. However, within-class differences linked to different chemical structures and/or drug potencies may exist, with a possible effect of the enalapril and lisinopril sub-groups in reducing the risk of incident MCI.
PMCID: PMC3592955  PMID: 22203459
Angiotensin-converting enzyme inhibitors; Mild cognitive impairment; Dementia; Antihypertensive drugs
4.  Systemic Oxidative Stress and Conversion to Dementia of Elderly Patients with Mild Cognitive Impairment 
BioMed Research International  2014;2014:309507.
Mild cognitive impairment (MCI) is regarded as a prodromal phase of late onset Alzheimer's disease (LOAD). It has been proposed that oxidative stress (OxS) might be implicated in the pathogenesis of LOAD. The aim of this study was to investigate whether a redox imbalance measured as serum level of hydroperoxides (i.e., by-products of lipid peroxidation) and/or serum antioxidant capacity might be predictive of the clinical progression of MCI to LOAD. The levels of these two markers were measured in 111 patients with MCI (follow-up: 2.0 ± 0.6 years), 105 patients with LOAD, and 118 nondemented healthy controls. Multivariate analysis adjusted for potential confounding factors, including age, gender, smoking, and comorbidities, showed a significant increase (P < 0.05) in baseline levels of OxS in MCI and LOAD as compared to cognitive healthy controls. No differences in either of OxS markers were found by comparing MCI patients who converted (n = 29) or not converted (n = 82) to LOAD. Overall, these results suggest that systemic OxS might be a precocious feature of MCI and LOAD. However, the role of OxS as an early prognostic marker of progression to LOAD needs further investigations.
PMCID: PMC3913282  PMID: 24524075
5.  Nutrition, frailty, and Alzheimer's disease 
PMCID: PMC4143595  PMID: 25206332
frailty and cognitive impairment; nutritional status; Alzheimer's disease; cognition disorders; dementia
6.  Klotho locus, metabolic traits, and serum hemoglobin in hospitalized older patients: a genetic association analysis 
Age  2011;34(4):949-968.
Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single-nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65–99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity.
PMCID: PMC3682056  PMID: 21695423
Klotho; Chromosome 13; High-density lipoprotein cholesterol; Total cholesterol; Fasting glucose; Fasting insulin; Insulin-like growth factor-1; Hemoglobin; Creatinine; Albumin; Lymphocytes
7.  Frailty syndrome and all-cause mortality in demented patients: the Italian Longitudinal Study on Aging 
Age  2011;34(2):507-517.
Cognition has already been considered as a component of frailty, and it has been demonstrated that it is associated with adverse health outcomes. We estimated the prevalence of frailty syndrome in an Italian older population and its predictive role on all-cause mortality and disability in nondemented subjects and in demented patients. We evaluated 2,581 individuals recruited from the Italian Longitudinal Study on Aging, a population-based sample of 5,632 subjects, aged 65–84 years old. Participants received identical baseline evaluation at the 1st survey (1992–1993) and were followed at 2nd (1995–1996) and 3rd survey (2000–2001). A phenotype of frailty according to partially modified measurement of Cardiovascular Health Study criteria was operationalized. The overall prevalence of frailty syndrome in this population-based study was 7.6% (95% confidence interval (CI) 6.55–8.57). Frail individuals noncomorbid or nondisable were 9.1% and 39.3%, respectively, confirming an overlap but not concordance in the co-occurrence among these conditions. Frailty was associated with a significantly increased risk of all-cause mortality over a 3-year follow-up (hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.52–2.60) and over a 7-year follow-up (HR 1.74, 95% CI 1.44–2.16), but with significant increased risk of disability only over a 3-year follow-up (HR 1.32, 95% CI 1.06–1.86 over a 3-year follow-up and HR 1.16, 95% CI 0.88–1.56 over a 7-year follow-up). Frail demented patients were at higher risk of all-cause mortality over 3- (HR 3.33, 95% CI 1.28–8.29) and 7-year follow-up periods (HR 1.89, 95% CI 1.10–3.44), but not of disability. Frailty syndrome was a short-term predictor of disability in nondemented older subjects and short- and long-term predictor of all-cause mortality in nondemented and demented patients.
PMCID: PMC3312634  PMID: 21519879
Frailty; All-cause mortality; Dementia; Disability; Alzheimer’s disease
Molecular psychiatry  2011;16(9):903-907.
Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios (ORs) alone are insufficient to assess these risks. We calculated AD lifetime risk in 7,351 cases and 10,132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68% and 35 % for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age- groups clearly demonstrates that APOE4 is a risk factor not only for late- onset but for early- onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.
PMCID: PMC3162068  PMID: 21556001
9.  Angiotensin-converting enzyme (ACE) genotypes and disability in hospitalized older patients 
Age  2010;33(3):409-419.
The association between angiotensin-converting enzyme (ACE) genotypes and functional decline in older adults remains controversial. To assess if ACE gene variations influences functional abilities at older age, the present study explored the association between the common ACE insertion/deletion (I/D) polymorphism and disability measured with activities of daily living (ADL) in hospitalized older patients. We analyzed the frequency of the ACE genotypes (I/I, I/D, and D/D) in a population of 2,128 hospitalized older patients divided according to presence or absence of ADL disability. Logistic regression analysis adjusted for possible confounding factors, identified an association between the I/I genotype with ADL disability (OR = 1.54, 95% CI 1.04–2.29). This association was significant in men (OR = 2.01, 95% CI 1.07–3.78), but not in women (OR = 1.36, 95% CI 0.82–2.25). These results suggested a possible role of the ACE polymorphism as a genetic marker for ADL disability in hospitalized older patients.
PMCID: PMC3168594  PMID: 21076879
Angiotensin-converting enzyme; Disability; Aging; Hospitalized patients
10.  Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer’s disease risk 
Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer’s disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs – rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex – levels of total soluble Aβ, oligomeric Aβ1-42, and guanidine-extractable (insoluble) Aβ – in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.
PMCID: PMC3316445  PMID: 22493749
Neprilysin; MME; gene; association; β-Amyloid; alzheimer disease; polymorphism
11.  Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease 
Hollingworth, Paul | Harold, Denise | Sims, Rebecca | Gerrish, Amy | Lambert, Jean-Charles | Carrasquillo, Minerva M | Abraham, Richard | Hamshere, Marian L | Pahwa, Jaspreet Singh | Moskvina, Valentina | Dowzell, Kimberley | Jones, Nicola | Stretton, Alexandra | Thomas, Charlene | Richards, Alex | Ivanov, Dobril | Widdowson, Caroline | Chapman, Jade | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K | Brayne, Carol | Rubinsztein, David C | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Brown, Kristelle S | Passmore, Peter A | Craig, David | McGuinness, Bernadette | Todd, Stephen | Holmes, Clive | Mann, David | Smith, A David | Beaumont, Helen | Warden, Donald | Wilcock, Gordon | Love, Seth | Kehoe, Patrick G | Hooper, Nigel M | Vardy, Emma R. L. C. | Hardy, John | Mead, Simon | Fox, Nick C | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Schürmann, Britta | Rüther, Eckart | Heun, Reiner | Kölsch, Heike | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Gallacher, John | Rujescu, Dan | Giegling, Ina | Goate, Alison M | Kauwe, John S K | Cruchaga, Carlos | Nowotny, Petra | Morris, John C | Mayo, Kevin | Sleegers, Kristel | Bettens, Karolien | Engelborghs, Sebastiaan | De Deyn, Peter P | Van Broeckhoven, Christine | Livingston, Gill | Bass, Nicholas J | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Al-Chalabi, Ammar | Shaw, Christopher E | Tsolaki, Magda | Singleton, Andrew B | Guerreiro, Rita | Mühleisen, Thomas W | Nöthen, Markus M | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Pankratz, V Shane | Sando, Sigrid B | Aasly, Jan O | Barcikowska, Maria | Wszolek, Zbigniew K | Dickson, Dennis W | Graff-Radford, Neill R | Petersen, Ronald C | van Duijn, Cornelia M | Breteler, Monique MB | Ikram, M Arfan | DeStefano, Anita L | Fitzpatrick, Annette L | Lopez, Oscar | Launer, Lenore J | Seshadri, Sudha | Berr, Claudine | Campion, Dominique | Epelbaum, Jacques | Dartigues, Jean-François | Tzourio, Christophe | Alpérovitch, Annick | Lathrop, Mark | Feulner, Thomas M | Friedrich, Patricia | Riehle, Caterina | Krawczak, Michael | Schreiber, Stefan | Mayhaus, Manuel | Nicolhaus, S | Wagenpfeil, Stefan | Steinberg, Stacy | Stefansson, Hreinn | Stefansson, Kari | Snædal, Jon | Björnsson, Sigurbjörn | Jonsson, Palmi V. | Chouraki, Vincent | Genier-Boley, Benjamin | Hiltunen, Mikko | Soininen, Hilkka | Combarros, Onofre | Zelenika, Diana | Delepine, Marc | Bullido, Maria J | Pasquier, Florence | Mateo, Ignacio | Frank-Garcia, Ana | Porcellini, Elisa | Hanon, Olivier | Coto, Eliecer | Alvarez, Victoria | Bosco, Paolo | Siciliano, Gabriele | Mancuso, Michelangelo | Panza, Francesco | Solfrizzi, Vincenzo | Nacmias, Benedetta | Sorbi, Sandro | Bossù, Paola | Piccardi, Paola | Arosio, Beatrice | Annoni, Giorgio | Seripa, Davide | Pilotto, Alberto | Scarpini, Elio | Galimberti, Daniela | Brice, Alexis | Hannequin, Didier | Licastro, Federico | Jones, Lesley | Holmans, Peter A | Jonsson, Thorlakur | Riemenschneider, Matthias | Morgan, Kevin | Younkin, Steven G | Owen, Michael J | O’Donovan, Michael | Amouyel, Philippe | Williams, Julie
Nature genetics  2011;43(5):429-435.
We sought to identify new susceptibility loci for Alzheimer’s disease (AD) through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer’s Disease Genetic Consortium (ADGC). First, we undertook a combined analysis of four genome-wide association datasets (Stage 1) and identified 10 novel variants with P≤1×10−5. These were tested for association in an independent sample (Stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (Stage 3). Meta-analyses of all data provide compelling evidence that ABCA7 (meta-P 4.5×10−17; including ADGC meta-P=5.0×10−21) and the MS4A gene cluster (rs610932, meta-P=1.8×10−14; including ADGC meta-P=1.2×10−16; rs670139, meta-P=1.4×10−9; including ADGC meta-P=1.1×10−10) are novel susceptibility loci for AD. Second, we observed independent evidence for association for three suggestive loci reported by the ADGC GWAS, which when combined shows genome-wide significance: CD2AP (GERAD+ P=8.0×10−4; including ADGC meta-P=8.6×10−9), CD33 (GERAD+ P=2.2×10−4; including ADGC meta-P=1.6×10−9) and EPHA1 (GERAD+ P=3.4×10−4; including ADGC meta-P=6.0×10−10). These findings support five novel susceptibility genes for AD.
PMCID: PMC3084173  PMID: 21460840
12.  Apolipoprotein E-related all-cause mortality in hospitalized elderly patients 
Age  2010;32(3):411-420.
The most common apolipoprotein E (APOE) allelic variation is implicated in many age-related diseases and human longevity with controversial findings. We investigated the effect of APOE gene polymorphism on all-cause mortality in elderly patients taking into consideration the functional disability, cognitive impairment, malnutrition, and the occurrence of common age-related diseases. APOE genotypes were determined in 2,124 geriatric hospitalized patients (46.5% men and 53.5% women; mean age, 78.2 ± 7.1 years; range, 65–100 years). At hospital admission, all patients underwent a comprehensive geriatric assessment to evaluate functional disability, cognitive status, nutritional status, and comorbidity. The main and secondary diagnoses at hospital discharge were also recorded. Mortality status was evaluated in all patients after a maximum follow-up of 5 years (range, from 1.26 to 5.23 years; median, 2.86 years). During the study period, 671 patients died (32.0%). At hospital admission, these patients showed a significant higher prevalence of cardiovascular diseases (56.3% vs 53.4%; p = 0.007), neoplasias (32.3% vs 13.7%; p < 0.001), and lower prevalence of neurodegenerative diseases (17.7% vs 20.7%; p < 0.001) than survived patients. Moreover, they also showed an higher prevalence of disability (52.0% vs 25.6%; p < 0.001), cognitive impairment (31.0% vs 18.8%; p < 0.001), and malnutrition (74.0% vs 46.1%; p < 0.001) than survived patients. In the overall study population, the APOE ε2 allele was significantly associated to neurodegenerative diseases (odds ratio = 0.59; 95% confidence interval (CI), 0.37–0.94). No significant association between the APOE polymorphism and disability, malnutrition, co-morbidity status, and with all-cause mortality was observed. In patients with cardiovascular diseases, however, a decreased risk of all-cause mortality was found in the ε2 allele carriers (hazard ratio = 0.56; 95% CI, 0.36–0.88). In this population, APOE allele variants might play a role on cardiovascular disease-related mortality.
PMCID: PMC2926860  PMID: 20640544
Apolipoprotein E; Mortality; Cardiovascular aging; Dementia
13.  Neuropsychiatric Symptoms, Endophenotypes, and Syndromes in Late-Onset Alzheimer's Disease: Focus on APOE Gene 
Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ε4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies.
PMCID: PMC3090058  PMID: 21559196
14.  The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer’s disease: a meta-analysis study 
Lambert, Jean-Charles | Sleegers, Kristel | González-Pérez, Antonio | Ingelsson, Martin | Beecham, Gary W | Hiltunen, Mikko | Combarros, Onofre | Bullido, Maria J | Brouwers, Nathalie | Bettens, Karolien | Berr, Claudine | Pasquier, Florence | Richard, Florence | DeKosky, Steven T | Hannequin, Didier | Haines, Jonathan L | Tognoni, Gloria | Fiévet, Nathalie | Dartigues, Jean-François | Tzourio, Christophe | Engelborghs, Sebastiaan | Arosio, Beatrice | Coto, Elicer | De Deyn, Peter | Zompo, Maria Del | Mateo, Ignacio | Boada, Merce | Antunez, Carmen | Lopez-Arrieta, Jesus | Epelbaum, Jacques | Schjeide, Brit-Maren Michaud | Frank-Garcia, Ana | Giedraitis, Vilmentas | Helisalmi, Seppo | Porcellini, Elisa | Pilotto, Alberto | Forti, Paola | Ferri, Raffaele | Delepine, Marc | Zelenika, Diana | Lathrop, Mark | Scarpini, Elio | Siciliano, Gabriele | Solfrizzi, Vincenzo | Sorbi, Sandro | Spalletta, Gianfranco | Ravaglia, Giovanni | Valdivieso, Fernando | Vepsäläinen, Saila | Alvarez, Victoria | Bosco, Paolo | Mancuso, Michelangelo | Panza, Francesco | Nacmias, Benedetta | Bossù, Paola | Hanon, Olivier | Piccardi, Paola | Annoni, Giorgio | Mann, David | Marambaud, Philippe | Seripa, Davide | Galimberti, Daniela | Tanzi, Rudolph E | Bertram, Lars | Lendon, Corinne | Lannfelt, Lars | Licastro, Federico | Campion, Dominique | Pericak-Vance, Margaret A | Soininen, Hilkka | Van Broeckhoven, Christine | Alpérovitch, Annick | Ruiz, Agustin | Kamboh, M Ilyas | Amouyel, Philippe
The only established genetic determinant of non-Mendelian forms of Alzheimer’s disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centres in Belgium, Finland, France, Italy, Spain, Sweden, the UK and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age at onset by interacting with the effect of the ε4 allele of the APOE gene.
PMCID: PMC2964875  PMID: 20847397
15.  Association of Apolipoprotein E and Angiotensin Converting Enzyme Gene Polymorphisms with the Multidimensional Impairment in Older Patients 
Rejuvenation research  2009;12(4):239-247.
The role of the apoliprotein E (APOE) and the angiotensin converting enzyme (ACE) polymorphisms on health and functional status deterioration in old age is still undefined. Recently, a Multidimensional Prognostic Index (MPI) for 1-year mortality derived from a Comprehensive Geriatric Assessment (CGA) was developed and validated in hospitalized elderly patients. The aim of this study was to investigate the possible association of the APOE and ACE gene polymorphisms with the multidimensional impairment, as evaluated by the MPI, in older patients. These polymorphisms were assessed in 1894 geriatric inpatients divided into three groups according to their MPI values: MPI-1 low risk (n = 988), MPI-2 moderate risk (n = 671), and MPI-3 severe risk of mortality (n = 235). A slight deviation from Hardy–Weinberg equilibrium was observed for the APOE genotypes. With the increasing of the MPI grade, a significant increase in the frequencies of ε4 allele and the ACE D/D genotype was observed. The APOE ε4+ and ACE D/D genotypes were associated with severe MPI grade (APOE ε4+, odds ration [OR] = 1.79, 95% confidence interval [CI] 1.20–2.67; ACE D/D, OR = 1.42, 95% CI 1.05–1.92). The combined APOE ε4+ and ACE D/D genetic status was associated with higher MPI grade (OR = 2.85, 95% CI 1.75–4.65), without interaction. No significant associations between APOE and ACE polymorphisms and 2-year mortality were found. APOE and ACE genes might predispose individuals to health and functional status deterioration in old age, and their effect is additive.
PMCID: PMC2868322  PMID: 19653879
16.  Association of Apolipoprotein E and Angiotensin Converting Enzyme Gene Polymorphisms with the Multidimensional Impairment in Older Patients 
Rejuvenation Research  2009;12(4):239-247.
The role of the apoliprotein E (APOE) and the angiotensin converting enzyme (ACE) polymorphisms on health and functional status deterioration in old age is still undefined. Recently, a Multidimensional Prognostic Index (MPI) for 1-year mortality derived from a Comprehensive Geriatric Assessment (CGA) was developed and validated in hospitalized elderly patients. The aim of this study was to investigate the possible association of the APOE and ACE gene polymorphisms with the multidimensional impairment, as evaluated by the MPI, in older patients. These polymorphisms were assessed in 1894 geriatric inpatients divided into three groups according to their MPI values: MPI-1 low risk (n = 988), MPI-2 moderate risk (n = 671), and MPI-3 severe risk of mortality (n = 235). A slight deviation from Hardy–Weinberg equilibrium was observed for the APOE genotypes. With the increasing of the MPI grade, a significant increase in the frequencies of ɛ4 allele and the ACE D/D genotype was observed. The APOE ɛ4+ and ACE D/D genotypes were associated with severe MPI grade (APOE ɛ4+, odds ration [OR] = 1.79, 95% confidence interval [CI] 1.20–2.67; ACE D/D, OR = 1.42, 95% CI 1.05–1.92). The combined APOE ɛ4+ and ACE D/D genetic status was associated with higher MPI grade (OR = 2.85, 95% CI 1.75–4.65), without interaction. No significant associations between APOE and ACE polymorphisms and 2-year mortality were found. APOE and ACE genes might predispose individuals to health and functional status deterioration in old age, and their effect is additive.
PMCID: PMC2868322  PMID: 19653879
17.  The Multidimensional Prognostic Index (MPI), Based on a Comprehensive Geriatric Assessment, Predicts Short- and Long-Term Mortality in Hospitalized Older Patients with Dementia 
Aim of this study was to evaluate the usefulness of a Multidimensional Prognostic Index (MPI) based on a Comprehensive Geriatric Assessment (CGA) for predicting mortality risk in older patients with dementia. The present was a retrospective study with a year of follow-up that included 262 patients aged 65 years and older with a diagnosis of dementia. A standardized CGA that included information on clinical, cognitive, functional, and nutritional aspects, as well as comorbidity, medications, and social support network, was used to calculate MPI. The predictive value of the MPI for all-cause mortality over 1 month, 6 months, and 12 months of follow-up was evaluated. Higher MPI values were significantly associated with higher mortality at 1 month (MPI-1, low risk = 0%, MPI-2, moderate risk = 5.2%, MPI-3, severe risk = 13.7%; p < 0.002), 6-months (MPI-1 = 2.7%, MPI-2 = 11.2%, MPI-3 = 28.8%; p < 0.001), and 12-months (MPI-1 = 2.7%, MPI-2 = 18.2%, MPI-3 = 35.6%; p < 0.001) of follow-up. The discrimination of the MPI was also good, with areas under the ROC curves of 0.77 (sensitivity = 82.9%, specificity = 66.0%, with a cut off value > 0.16) at 12-months of follow up. In conclusion, the MPI, calculated from information collected in a standardized CGA, accurately stratified hospitalized elderly patients with dementia into groups at varying risk of short- and long-term mortality.
PMCID: PMC2864495  PMID: 19584441
Comprehensive Geriatric Assessment (CGA); dementia; mortality; Multidimensional Prognostic Index (MPI); prognosis; survival
18.  LRP-1 variation is not associated with risk of Alzheimer's disease 
Alzheimer's disease (AD) is characterised by the extensive deposition of amyloid beta (Aβ) within the parenchyma and vasculature of the brain. It is hypothesised that a dysfunction in Aβ degradation and/or its removal from the brain may result in accumulation as plaques. Low density lipoprotein receptor-related protein-1 (LRP-1) is a multifunctional receptor shown to be involved in cholesterol metabolism but also the removal of Aβ from the brain. Its ability to transport Aβ from the brain to the periphery has made it an attractive candidate for involvement in Alzheimer's disease (AD). We have assessed the frequencies of 9 tag- SNPs and the commonly studied synonymous SNP within exon 3 (rs1799986) in a multi-centre AD/control cohort and performed haplotype analysis. We found no evidence from a combined total of 412 controls and 1057 AD patients to support the involvement of LRP-1 variation, including the most commonly studied variant in rs1799986 in conferring genetic susceptibility to increased risk of AD.
PMCID: PMC3076756  PMID: 21537384
LRP-1; Alzheimer's disease; association analysis
19.  The complex interaction between APOE promoter and AD: an Italian case–control study 
The single nucleotide polymorphisms (SNPs) rs449647, rs769446 and rs405509 in the promoter region of the APOE gene have been variously suggested to be ɛ4-independent risk factors for Alzheimer's disease (AD). A previous Italian study found that the rs449647 was significantly associated with late-onset AD. The aim of this study was to verify whether these APOE promoter SNPs are genetic risk factors for AD and to investigate their interaction with the common APOE polymorphism. A total of 169 clinically diagnosed AD patients and 99 cognitively intact age-matched controls were included in the study. Significant associations with AD independent from sex, age and APOE/ɛ4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). Haplotype frequency estimation at the APOE locus showed significant associations for the ATG4, ATT4 and ACG3 (positive) and ATT2, ATT3 and TCG3 (negative) haplotypes. Therefore this study confirms the role of the rs449647 A/A genotype as risk factor for AD in Italy and suggests that promoter genotypes and APOE haplotypes might have a complex function in AD-associated genetic risk factors.
PMCID: PMC2986491  PMID: 19172988
APOE promoter; haplotypes; Alzheimer's disease; genetic risk factors
20.  Development and Validation of a Multidimensional Prognostic Index for One-Year Mortality from Comprehensive Geriatric Assessment in Hospitalized Older Patients 
Rejuvenation research  2008;11(1):151-161.
Our objective was to construct and validate a Multidimensional Prognostic Index (MPI) for 1-year mortality from a Comprehensive Geriatric Assessment (CGA) routinely carried out in elderly patients in a geriatric acute ward. The CGA included clinical, cognitive, functional, nutritional, and social parameters and was carried out using six standardized scales and information on medications and social support network, for a total of 63 items in eight domains. A MPI was developed from CGA data by aggregating the total scores of the eight domains and expressing it as a score from 0 to 1. Three grades of MPI were identified: low risk, 0.0–0.33; moderate risk, 0.34–0.66; and severe risk, 0.67–1.0. Using the proportional hazard models, we studied the predictive value of the MPI for all causes of mortality over a 12-month follow-up period. MPI was then validated in a different cohort of consecutively hospitalized patients. The development cohort included 838 and the validation cohort 857 elderly hospitalized patients. Of the patients in the two cohorts, 53.3 and 54.9% were classified in the low-risk group, respectively (MPI mean value, 0.18 ± 0.09 and 0.18 ± 0.09); 31.2 and 30.6% in the moderate-risk group (0.48 ± 0.09 and 0.49 ± 0.09); 15.4 and 14.2% in the severe-risk group (0.77 ± 0.08 and 0.75 ± 0.07). In both cohorts, higher MPI scores were significantly associated with older age (p = 0.0001), female sex (p = 0.0001), lower educational level (p = 0.0001), and higher mortality (p = 0.0001). In both cohorts, a close agreement was found between the estimated mortality and the observed mortality after both 6 months and 1 year of follow-up. The discrimination of the MPI was also good, with a ROC area of 0.751 (95%CI, 0.70–0.80) at 6 months and 0.751 (95%CI, 0.71–0.80) at 1 year of follow-up. We conclude that this MPI, calculated from information collected in a standardized CGA, accurately stratifies hospitalized elderly patients into groups at varying risk of mortality.
PMCID: PMC2668166  PMID: 18173367
21.  Usefulness of the Comprehensive Geriatric Assessment in Older Patients with Upper Gastrointestinal Bleeding: A Two-Year Follow-Up Study 
The potential usefulness of standardized comprehensive geriatric assessment (CGA) in evaluating treatment and follow-up of older patients with upper gastrointestinal bleeding is unknown.
To evaluate the usefulness of the CGA as a 2-year mortality multidimensional prognostic index (MPI) in older patients hospitalized for upper gastrointestinal bleeding.
Materials and Methods
Patients aged ≥65 years consecutively hospitalized for acute upper gastrointestinal bleeding were included. Diagnosis of bleeding was based on clinical and endoscopic features. All patients underwent a CGA that included six standardized scales, i.e., Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Short Portable Mental Status Questionnaire (SPMSQ), Mini Nutritional Assessment (MNA), Exton-Smith Score (ESS) and Comorbity Index Rating Scale (CIRS), as well as information on medication history and cohabitation, for a total of 63 items. A MPI was calculated from the integrated total scores and expressed as MPI 1 = low risk, MPI 2 = moderate risk, and MPI 3 = severe risk. The predictive value of the MPI for mortality over a 24-month follow-up was calculated.
36 elderly patients (M 16/F 20, mean age 82.8 ± 7.9 years, range 70–101 years) were included in the study. A significant difference in mean age was observed between males and females (M 80.1 ± 4.8 vs. F 84.9 ± 9.3 years; p < 0.05). The causes of upper gastrointestinal bleeding were duodenal ulcer in 38.8%, gastric ulcer in 22.2%, and erosive gastritis in 16.6% of the patients, while 16.6% had gastrointestinal bleeding from unknown origin. The overall 2-year mortality rate was 30.5%. 18 patients (50%) were classified as having a low-risk MPI (mean value 0.18 ± 0.09), 12 (33.3%) as having a moderate-risk MPI (mean value 0.48 ± 0.08) and 6 (16.6%) as having a severe-risk MPI (mean value 0.83 ± 0.06). Higher MPI grades were significantly associated with higher mortality (grade 1 = 12.5%, grade 2 = 41.6%, grade 3 = 83.3%; p = 0.001). Adjusting for age and sex, the prognostic efficacy of MPI for mortality was confirmed and highly significant (odds ratio 10.47, 95% CI 2.04–53.6).
CGA is a useful tool for calculating a MPI that significantly predicts the risk of 2-year mortality in older patients with upper gastrointestinal bleeding.
PMCID: PMC2645635  PMID: 17468547
Comprehensive geriatric assessment; Multidimensional prognostic index; Upper gastrointestinal bleeding; diagnosis

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