Showing papers by "Diego Albani published in 2013"

Body mass index, lifestyles, physical performance and cognitive decline: the "Treviso Longeva (TRELONG)" study.

Abstract: Objectives The relative contributions of risk factors, as body mass index (BMI), depression, chronic diseases, smoking, and lifestyles (as physical and performance activity, social contacts and reading habit) to cognitive decline in the elderly are unclear We explored these variables in relation to 7-year cognitive decline in long-lived Italian elderly

C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: a genotype-phenotype correlation study.

Abstract: Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201) Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier In our cohort, the C9ORF72 pathological expansion: (i) showed a prevalence of 75%; (ii) showed a full penetrance by the age of 80; (iii) was rarely found in sporadic patients; (iv) was solely associated with FTLD; (v) was mainly associated with bvFTD clinical subtype; and (vi) was associated with earlier age of onset in the youngest generation compared with the previous generation within a pedigree Interestingly, intermediate C9ORF72 expansion had a risk effect in familial/sporadic FTLD Eventually, the C9ORF72 repeat units number influenced the disease phenotype in terms of age of onset and associated clinical subtype Genome-wide studies in well characterized clinical cohorts will be essential in order to decipher pathways of disease expression in C9ORF72-associated neurodegeneration

The SIRT2 polymorphism rs10410544 and risk of Alzheimer's disease in two Caucasian case-control cohorts.

Abstract: Background Human sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimer's disease (AD). This study investigated whether genetic variants in two members of the sirtuin family, SIRT2 and SIRT3 , affected AD susceptibility. Methods A genetic case–control study was performed, comprising 534 probable AD cases and 638 nondemented control subjects from the north of Italy and Canton Ticino, Switzerland (discovery population). The study was focused on SIRT2 rs10410544, SIRT3 rs4980329, and SIRT3 rs536715 single nucleotide polymorphisms (SNPs). These SNPs were genotyped by real-time polymerase chain reaction allelic discrimination assay or restriction fragment length polymorphism. The SNPs rs7412 and rs429358, mapping within the apolipoprotein E ( APOE ) gene, were genotyped by real-time polymerase chain reaction allelic discrimination assay too. In a replication population comprising 756 AD cases and 847 nondemented control subjects, SIRT2 rs10410544, APOE rs7412, and APOE rs429358 were genotyped as mentioned previously. Results In the discovery population, we observed an association between SIRT2 rs10410544 T allele and AD (adjusted odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.02–1.50, P = .02, after correction for sex, age, and APOE ɛ4 genotype). The association between AD and SIRT2 rs10410544 T allele was only present in APOE ɛ4 noncarriers (adjusted OR=1.29, 95% CI: 1.03–1.61, P = .03). The replication study did not confirm this evidence. However, the combined analysis on the two cohorts detected the association (adjusted OR=1.17, 95% CI: 1.02–1.35, P = .02), and only APOE ɛ4 noncarriers were at risk (adjusted OR=1.2, 95% CI: 1.02–1.43, P = .03). Conclusions The SIRT2 rs10410544 T allele deserves further investigation as a novel minor genetic risk factor for AD in the APOE ɛ4-negative Caucasian population.

Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients

Abstract: Treatment resistant depression (TRD) is a significant clinical and public health problem. Among others, neuroplasticity and inflammatory pathways seem to play a crucial role in the pathomechanisms of antidepressant efficacy. The primary aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within two genes implicated in neuroplasticity and inflammatory processes (the mitogen activated protein kinase 1, MAPK1 (rs3810608, rs6928, rs13515 and rs8136867), and the cyclic AMP responsive element binding protein 1, CREB1 (rs889895, rs6740584, rs2551922 and rs2254137)) was associated with antidepressant treatment resistance (according to two different definitions), in 285 Major Depressive Disorder (MDD) patients. As secondary aims, we investigated the genetic modulation of the same SNPs on response, remission and other clinical features both in MDD patients and in a larger sample including 82 Bipolar Disorder (BD) patients as well. All patients were screened in the context of a European multicenter project. No association between both the investigated genes and treatment resistance and response was found in MDD patients. However, considering remission, higher rates of CREB1 rs889895 GG genotype were reported in MDD patients. Moreover, MAPK1 rs8136867 AG genotype was found to be associated with remission in the whole sample (MDD and BD). Present results suggest that some genetic polymorphisms in both CREB1 and MAPK1 could be associated with treatment remission. Although further research is needed to draw more definitive conclusions, such results are intriguing since suggest a potential role of two genes implicated in neuroplasticity and inflammatory processes in symptom remission after antidepressant treatment.

Association between Sirtuin 2 gene rs10410544 polymorphism and depression in Alzheimer's disease in two independent European samples.

Abstract: Among the several genes associated with late-onset Alzheimer’s disease (LOAD), recently, Sirtuin genes have roused a growing interest because of their involvement in metabolic homeostasis and in brain aging. Particularly SIRT2 gene has been associated with Alzheimer’s disease (AD) as well as with mood disorders. The aim of this study is to investigate the possible associations between Sirtuin 2 gene (SIRT2) rs10410544 polymorphism and AD as well as depression in AD. In addition, we performed some exploratory analyses to investigate possible associations between the rs10410544 genotype and clinical features. We investigated these associations in two independent samples: the first one was composed of 275 Greek inhabitants and 117 patients; the second sample counted 181 Italian people and 43 patients. All patients were affected by LOAD. We failed to find any association between rs10410544 genotype and AD in the two samples. On the other hand, we found an association between the single nucleotide polymorphism (SNP) and depressive symptomatology (in the total sample p = 0.002), which was modulated by the tumor necrosis factor (TNF) values. Particularly, TT genotype seems to be protective versus depression. Finally, in the exploratory analyses, we found that the TT genotype was associated with earlier AD onset and a longer duration of the illness. In conclusion, we confirmed the association between SIRT2 gene and mood disturbances, although in AD patients. Further, we provided evidence that the TT genotype may be protective versus depressive symptoms, allowing an easier and thus earlier diagnosis of AD. This awareness may lead to a more detailed approach to these patients concerning diagnosis and therapy.

Hydrogel-Based Nanocomposites and Mesenchymal Stem Cells: A Promising Synergistic Strategy for Neurodegenerative Disorders Therapy

Abstract: Hydrogel-based materials are widely employed in the biomedical field. With regard to central nervous system (CNS) neurodegenerative disorders, the design of injectable nanocomposite hydrogels for in situ drug or cell release represents an interesting and minimally invasive solution that might play a key role in the development of successful treatments. In particular, biocompatible and biodegradable hydrogels can be designed as specific injectable tools and loaded with nanoparticles (NPs), to improve and to tailor their viscoelastic properties upon injection and release profile. An intriguing application is hydrogel loading with mesenchymal stem cells (MSCs) that are a very promising therapeutic tool for neurodegenerative or traumatic disorders of the CNS. This multidisciplinary review will focus on the basic concepts to design acellular and cell-loaded materials with specific and tunable rheological and functional properties. The use of hydrogel-based nanocomposites and mesenchymal stem cells as a synergistic strategy for nervous tissue applications will be then discussed.

One single method to produce native and Tat-fused recombinant human α-synuclein in Escherichia coli.

Abstract: Human α-synuclein is a small-sized, natively unfolded protein that in fibrillar form is the primary component of Lewy bodies, the pathological hallmark of Parkinson’s disease. Experimental evidence suggests that α-synuclein aggregation is the key event that triggers neurotoxicity although additional findings have proposed a protective role of α-synuclein against oxidative stress. One way to address the mechanism of this protective action is to evaluate α-synuclein-mediated protection by delivering this protein inside cells using a chimeric protein fused with the Tat-transduction domain of HIV Tat, named TAT-α-synuclein. A reliable protocol was designed to efficiently express and purify two different forms of human α-synuclein. The synthetic cDNAs encoding for the native α-synuclein and the fusion protein with the transduction domain of Tat protein from HIV were overexpressed in a BL21(DE3) E. coli strain as His-tagged proteins. The recombinant proteins largely localized (≥ 85%) to the periplasmic space. By using a quick purification protocol, based on recovery of periplasmic space content and metal-chelating chromatography, the recombinant α-synuclein protein forms could be purified in a single step to ≥ 95% purity. Both α-synuclein recombinant proteins form fibrils and the TAT-α-synuclein is also cytotoxic in the micromolar concentration range. To further characterize the molecular mechanisms of α-synuclein neurotoxicity both in vitro and in vivo and to evaluate the relevance of extracellular α-synuclein for the pathogenesis and progression of Parkinson’s disease, a suitable method to produce different high-quality forms of this pathological protein is required. Our optimized expression and purification procedure offers an easier and faster means of producing different forms (i.e., both the native and the TAT-fusion form) of soluble recombinant α-synuclein than previously described procedures.

Effects of SORL1 gene on Alzheimer's disease. Focus on gender, neuropsychiatric symptoms and pro-inflammatory cytokines.

Abstract: It was suggested that the gene encoding for sorLa, (SORL1) may affect Alzheimer's disease (LOAD) through a female-specific mechanism. The aims of this study were to confirm the role of gender in modulating the association between SORL1 and LOAD and to ascertain the influence of SORL1 on cognitive impairment, neuropsychiatric symptoms (BPSD) and secretion of pro-inflammatory cytokines. Ninety six outpatients with LOAD and 120 unrelated controls were genotyped for APOE and three SNPs at the 5' end of SORL1(intron 6): SNP 8 (rs668387); SNP 9 (rs68902); SNP 10 (rs641120). Clinical evaluation was made with the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). ELISPOT assays were used to measure pro-inflammatory cytokine (TNF-alpha; IL-6; IL-1beta; IFN-gamma) production in peripheral blood mononuclear cell (PBMC) supernatant from AD patients. SORL1 SNPs were not associated with LOAD in overall sample. Instead the G-alleles at SNPs 9 (p=0.015) and 10 (p=0.015) and the CGG haplotype (p=0.02) were associated with LOAD in the women subgroup. The TAA haplotype was marginally protective in AD patients being associated with lower BPSD scores (p=0.01). The same haplotype was also associated with higher IL-1beta (p=0.01) production. These genetic effects were not modified by APOE4 allele and controlled for illness duration and treatment. In conclusion, SORL1 does not appear to be a major risk factor for LOAD. Its contribution could be underestimated in our small sample. Sex-specific factors could modulate the association between SORL1 and AD. The influence of SORL1 variants on production of inflammatory cytokines warrants further investigation.

Development and analysis of semi-interpenetrating polymer networks for brain injection in neurodegenerative disorders.

Abstract: PurposeOur aim was to assess the use of injectable, biocompatible and resorbable, hydrogel-based tools for innovative therapies against brain-related neurodegenerative disorders like Alzheimer's (A...

Multiplex assessment of a panel of 16 serum molecules for the differential diagnosis of Alzheimer's disease.

Abstract: One of the current challenge in Alzheimer’s disease (AD) is the identification of reliable biomarkers that might improve diagnostic accuracy, possibly correlating with the disease progression and patient’s response to therapy. As the clinically validated AD biomarkers evaluate cerebrospinal fluid (CSF) parameters, the need for less invasive diagnostic markers is well evident. To this respect, blood circulating cytokines or growth factors have provided some encouraging results, even though no clinically validated to date. In 2007 Ray et al suggested a panel of 18 circulating molecules that might increase AD diagnostic accuracy. In an attempt of replicating their data, we designed a multiplex fluorimetric assay comprising 16 independent analytes and covering 15 out of the 18 described proteins. We collected serum samples from three diagnostic groups: probable AD (n=33), matched healthy controls (CNT, n=23) and non AD demented (NAD, n=14). After correction for age, we found an increased level of EGF-1 in AD in comparison to CNT and NAD, while an increase of TRAIL-R4 was found in NAD. However, evaluation of specificity/sensitivity by ROC curve analysis gave weak evidence of diagnostic accuracy (area under the curve = 0.63 and 0.66 for EGF and TRAIL-R4, respectively). Finally, we tried to find a diagnostic classifier by a multivariate algorithm. We found indication of diagnostic evidence for AD only, while NAD samples did not show a diagnostic pattern.

Impact of 5-HTTLPR polymorphism on alexithymia in alcoholic patients after detoxification treatment.

Abstract: Alexithymia symptoms have been reported in individuals suffering from alcohol abuse and other substance use disorders (SUDs) (Thorberg et al., 2009; Malat et al., 2010). However, alexithymia does not seem to be a stable disorder in SUD patients; indeed, symptoms’ decline has been reported in some individuals after detoxification treatment (de Haan et al., 2012). A combination of genetic and environmental influences may contribute to individual differences in alexithymia (Baughman et al., 2011). Therefore, genetic factors may modulate the risk to develop alexithymia symptoms in SUD patients and the recovery from symptoms after detoxification. In a previous study, we investigated a set of genetic variants in detoxification outcome, taking into account also alexithymia (Serretti et al., 2006b). We observed a reduction of alexithymia symptoms after treatment but not dependently from genetic variants. In particular, reduction of alexithymia symptoms was not influenced by the biallelic length polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR long/short), a polymorphism that has received much interest in several psychopathologic dimensions,

APOE genotype and the risk of dementia in the oldest-old: The Monzino 80-plus study

Abstract: Background: The risks, prevention and epidemiology of Alzheimer’s disease continue to remain uncertain despite extensive research. A few modifiable risk and preventive factors, such as low education, obesity, smoking, physical inactivity, and certain hormone therapies, have been reported from epidemiological studies. However, many studies have been limited by methodological quality and relatively small sample sizes, typically involving up to a few hundred Alzheimer’s disease cases and a few thousand participants. Studies from large-scale population-based cohorts with extensive exposure assessment and sufficiently long followup are critically needed. We describe the California Teachers Study cohort, established in 1995 primarily for breast cancer research, as a developing resource for large-scale etiologic Alzheimer’s disease research. Methods: The California Teachers Study consists of 133,479 women who have provided extensive exposure data over their life course including most putative risk factors for Alzheimer’s disease. Four waves of questionnaires have been sent since 1995. In the year 2000, we included neuropsychological test items that focused on visuospatial and language function. Results: Active and retired California public school professionals provided information on environmental and lifestyle factors that may be important for Alzheimer’s disease risk, including obesity, physical and social activity, medical history, medications, hormone use, diet, and demographic factors. In 2000-2001, w78,000 participants completeda clock drawing, cube drawing, and picture description task. Of these, w35,000 were 70 years or older in 2010. Assessment of Alzheimer’s disease in the cohort can be done by database linkage to California statewide hos pitalization data, which includes diagnoses after hospitalization, emergency department visits, and outpatient surgery. Conclusions:Large cohorts are needed in order to pursue risk and prevention research in Alzheimer’s disease, as recommended by the 2010 NIH State-ofthe-Science expert consensus conference. The California Teachers Study provides extensive high quality information on mostpotential environmental and lifestyle risk and protective factors, and represents a robust cohort for epidemiologic research, as a resource to conduct timely analyses using accrued cases, and for prospective outcomes research in Alzheimer’s disease.

Original Article Multiplex assessment of a panel of 16 serum molecules for the differential diagnosis of Alzheimer's disease

Abstract: * These authors contributed equally to the work. Received January 15, 2013; Accepted February 5, 2013; Epub March 8, 2013; Published March 18, 2013 Abstract: One of the current challenge in Alzheimer's disease (AD) is the identification of reliable biomarkers that might improve diagnostic accuracy, possibly correlating with the disease progression and patient's response to therapy. As the clinically validated AD biomarkers evaluate cerebrospinal fluid (CSF) parameters, the need for less invasive diagnostic markers is well evident. To this respect, blood circulating cytokines or growth factors have pro- vided some encouraging results, even though no clinically validated to date. In 2007 Ray et al suggested a panel of 18 circulating molecules that might increase AD diagnostic accuracy. In an attempt of replicating their data, we de- signed a multiplex fluorimetric assay comprising 16 independent analytes and covering 15 out of the 18 described proteins. We collected serum samples from three diagnostic groups: probable AD (n=33), matched healthy controls (CNT, n=23) and non AD demented (NAD, n=14). After correction for age, we found an increased level of EGF-1 in AD in comparison to CNT and NAD, while an increase of TRAIL-R4 was found in NAD. However, evaluation of specificity/ sensitivity by ROC curve analysis gave weak evidence of diagnostic accuracy (area under the curve = 0.63 and 0.66 for EGF and TRAIL-R4, respectively). Finally, we tried to find a diagnostic classifier by a multivariate algorithm. We found indication of diagnostic evidence for AD only, while NAD samples did not show a diagnostic pattern.