Authors: Grassi, Mario | Voinovich, Dario | Grabnar, Iztok | Franceschinis, Erica | Perissutti, Beatrice | Filipovic‐Grcic, Jelena
Article Type: Research Article
Abstract: The potential of a sustained release formulation for paracetamol produced by melt pelletisation was investigated. After the production of the pellets, based on the combination of stearic acid as a melting binder and anhydrous lactose as a filler, the 3000–2000 μm size fraction was selected in the light of the promising in vitro dissolution results for further characterisations, including scanning electron microscopy (SEM), X‐ray photoelectron spectroscopy (XPS), specific surface area and true density determination. Hence the release mechanism was analysed with the help of an appropriate mathematical model. The mathematical model was built on the hypotheses that drug diffusion and …solid drug dissolution in the release environment are the key phenomena affecting drug release kinetics. Bioavailability of the developed formulation was evaluated in an in vivo study in eight subjects. Show more
Keywords: Melt pelletisation, high shear mixer, paracetamol, sustained release, in vitro dissolution, modelling of drug‐release mechanism, in vivo bioavailability studies
Citation: Spectroscopy, vol. 18, no. 2, pp. 375-386, 2004
Authors: Borroni, Barbara | Grassi, Mario | Premi, Enrico | Alberici, Antonella | Cosseddu, Maura | Cancelli, Vanessa | Caobelli, Federico | Paghera, Barbara | Padovani, Alessandro
Article Type: Research Article
Abstract: Prediction of survival in frontotemporal lobar degeneration (FTLD) is guesswork. The aim of the present study was to evaluate whether SPECT scan may be useful to predict prognosis of long term survival in FTLD patients. A cohort of 125 patients with FTLD who underwent brain SPECT scan at the time of enrollment and who were further followed up for at least one year were considered. In each subject, volume of interests (VOIs) covering frontotemporal and parietal regions, bilaterally, were drawn. Principal component analysis (PCA) was applied on VOIs, and a Cox regression model was carried out to find out best …predictors of survival. A two-pattern PCA solution was chosen, explaining more than 70% of variance, and “frontal” PC1 and “temporal” PC2 components were identified. The frontal PC1 was associated with higher rate of faster progression (HR = 2.06, 95% CI = 1.23–3.44, p = 0.006 for univariate model, and HR = 1.85, 95% CI = 1.04–3.28, p = 0.03 for multivariate model). In particular, right orbitofrontal cortex showed the higher loadings in PC1; the worse the scores of this region the shorter the survival was reported. We suggest that SPECT imaging, beyond a helpful tool in diagnostic assessment, may be an easily and accessible marker of disease outcome in FTLD. Further studies considering structural neuroimaging are warranted. Show more
Keywords: Frontotemporal lobar degeneration, neuroimaging, prognosis, progression, SPECT
DOI: 10.3233/JAD-2012-112078
Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 883-890, 2012
Authors: Borroni, Barbara | Grassi, Mario | Archetti, Silvana | Costanzi, Chiara | Bianchi, Marta | Caimi, Luigi | Caltagirone, Carlo | Di Luca, Monica | Padovani, Alessandro
Article Type: Research Article
Abstract: The gene encoding the brain-derived neurotrophic factor (BDNF) has been demonstrated as a candidate for Alzheimer's disease-related depression (AD-D) susceptibility. Additionally, an association between AD-D and the functional valine to methionine (Val66Met) polymorphism has been reported. The aim of this study was to assess the genetic contribution of other BDNF variants to AD-D. Two-hundred forty-five AD patients were divided into two subgroups according to the presence (AD-D) or the absence (AD-nD) of depressive symptoms. Four single-nucleotide polymorphisms within BDNF gene were considered, i.e., C270T, rs2049045 C/G, G196A (Val66Met), and G11757C. In our sample, 35.5% of patients (n = 87) reported …AD-related depressive symptoms. The individual SNP analysis showed an association between G196A and G11757C genotypes and AD-D. Accordingly, considering the allele frequencies, BDNF 196*A allele was significantly overrepresented in AD-D compared to AD-nD (OR = 1.80, 95% CI = 1.19–2.72), as well as BDNF 11757*C allele (OR = 1.90, 95% CI = 1.25–2.90). Haplotype analyses revealed that the alleles at four loci (C270T, rs2049045 C/G, G196A, G11757C) interacted to further increase the risk of AD-D. Compared to the most common not-at-risk C-C-G-G haplotype, C-G-A-C (OR = 3.55, 95% CI = 1.44–8.76, P = 0.006) and C-C-A-C haplotypes (OR = 1.72, 95% CI = 1.03–2.87, P = 0.037) were overrepresented in AD-D. This study suggests that BDNF genetic variations play a role in the susceptibility to AD-related depression. Show more
Keywords: Alzheimer's disease, brain-derived neurotrophic factor (BDNF), depression, genetics, haplotype, polymorphism
DOI: 10.3233/JAD-2009-1191
Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 867-875, 2009
Authors: Borroni, Barbara | Alberici, Antonella | Grassi, Mario | Turla, Marinella | Zanetti, Orazio | Bianchetti, Angelo | Volta, Giorgio Dalla | Rozzini, Renzo | Gilberti, Nicola | Bellelli, Giuseppe | Padovani, Alessandro
Article Type: Research Article
Abstract: Frontotemporal Lobar Degeneration (FTLD) has always been considered a rare disorder, but only a few epidemiologic studies are available. The aim of the present work was to ascertain all FTLD patients in a Northern Italy area from January 2001 to December 2008, and to estimate the disease prevalence. On the census day, 213 FTD patients were still alive, resulting in an overall prevalence of 17.6 per 100,000 inhabitants. The prevalence of FTLD in patients aged 45–65 years was 22 per 100,000 inhabitants (95% CI=17–27). The prevalence of FTLD was the highest in patients aged 66–75 (78 per 100,000 inhabitants, 95% …CI=56–100), and it was still high over 75 years (54 per 100,000 inhabitants, 95% CI=36–69). FTLD is a more common form of dementia than previously recognized. Our results claimed that FTLD is not only an early-onset disorder, but it is frequent in advanced age as well. Show more
Keywords: Epidemiology, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, prevalence, rare disease
DOI: 10.3233/JAD-2010-1208
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 111-116, 2010
Authors: Borroni, Barbara | Malinverno, Matteo | Gardoni, Fabrizio | Grassi, Mario | Parnetti, Lucilla | Agosti, Chiara | Alberici, Antonella | Premi, Enrico | Bonuccelli, Ubaldo | Gasparotti, Roberto | Calabresi, Paolo | Di Luca, Monica | Padovani, Alessandro
Article Type: Research Article
Abstract: Cerebrospinal fluid (CSF) tau ratio decrease (33kDa/55kDa forms) and mid-saggital midbrain-to-pons (MP) atrophy have been suggested as diagnostic markers for progressive supranuclear palsy (PSP). The usefulness of their combined evaluation has never been tested. We evaluated the CSF tau ratio and the MP atrophy as a combined marker for early identification of PSP. A total of 87 subjects, namely 18 PSP, 25 controls (CON), 16 corticobasal syndrome (CBS), and 28 frontotemporal dementia (FTD), were included. Each subject underwent a lumbar puncture and a conventional MRI scan to assess CSF tau 33 kDa/55 kDa ratio and mid-saggital MP measure, respectively. CSF …tau ratio and MP ratio were significantly reduced in PSP patients when compared to CON, CBS, and FTD (p< 0.001). Data-based “optimal” combination of CSF tau ratio and MP measure was defined, and the combined marker TrMp = CSF Tau ratio 3 × MP ratio was considered. Considering the combined marker, the difference between the area under the curve (dAUC) of the receiver operating characteristic analysis in PSP versus the various subgroups was higher by about 10% than that obtained by each marker individually. In PSP versus others, a proposed “best” cut-off of TrMP = 0.182 resulted in 94.2% sensitivity and 84.0% specificity. When patients with onset of symptoms ⩽ 2 years were included, TrMP resulted significantly decreased in PSP compared to CBS (p< 0.001) and FTD (p< 0.001). The combined marker increases the discriminative power in identifying PSP and suggests that the interplay of different markers should be considered in future trials to enhance diagnostic accuracy from the early stages. Show more
Keywords: Biological marker, cerebrospinal fluid, corticobasal syndrome, frontotemporal dementia, MRI, progressive supranuclear palsy, tau
DOI: 10.3233/JAD-2010-100333
Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 195-203, 2010
Authors: Ferrari, Raffaele | Grassi, Mario | Graziano, Francesca | Palluzzi, Fernando | Archetti, Silvana | Bonomi, Elisa | Bruni, Amalia C. | Maletta, Raffaele G. | Bernardi, Livia | Cupidi, Chiara | Colao, Rosanna | Rainero, Innocenzo | Rubino, Elisa | Pinessi, Lorenzo | Galimberti, Daniela | Scarpini, Elio | Serpente, Maria | Nacmias, Benedetta | Piaceri, Irene | Bagnoli, Silvia | Rossi, Giacomina | Giaccone, Giorgio | Tagliavini, Fabrizio | Benussi, Luisa | Binetti, Giuliano | Ghidoni, Roberta | Singleton, Andrew | Hardy, John | Momeni, Parastoo | Padovani, Alessandro | Borroni, Barbara
Article Type: Research Article
Abstract: In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide …polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by –3.86 (95% CI: –4.64 to –3.07, p < 2×10–16 ) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted. Show more
Keywords: Age at onset, frontotemporal dementia, GWAS, polymorphism
DOI: 10.3233/JAD-160949
Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1271-1278, 2017
Authors: Borroni, Barbara | Grassi, Mario | Bianchi, Marta | Bruni, Amalia Cecilia | Maletta, Raffaele Giovanni | Anfossi, Maria | Pepe, Daniele | Cagnin, Annachiara | Caffarra, Paolo | Cappa, Stefano | Clerici, Francesca | Daniele, Antonio | Frisoni, Giovanni B. | Galimberti, Daniela | Parnetti, Lucilla | Perri, Roberta | Rainero, Innocenzo | Tremolizzo, Lucio | Turla, Marinella | Zanetti, Orazio | Padovani, Alessandro
Article Type: Research Article
Abstract: Frontotemporal dementia (FTD) has a strong genetic basis, with familial forms occurring in 30–50% of cases. Causative genes have been identified, with an autosomal dominant pattern of inheritance. Notwithstanding, in a number of cases with positive family history no pathogenetic mutation has been reported, and the role of genetics in sporadic cases is still unclear. In the present study, we aim to estimate the genetic contribution to FTD using concordance among parent-offspring pairs. Heritability of early-onset (EO, <65 years) and late-onset (LO, ≥65 years) FTD was estimated by examining the concordance between parents and offspring. Probands with at least one …parent whose dementia status was known were recruited from 15 Italian centers, and the presence or absence of dementia was considered in siblings. Different prevalence estimates, as available by literature data, were tested. A total of 260 probands and 1619 family members were considered in this study. We found that parent-offspring concordance in FTD was 6.25%, resulting in hereditability of 98.5% (95% confidence interval (CI): 85.0%–100.0%). Equal heritability for both sexes regardless of parental gender was reported. EO-FTD showed hereditability of 86.3% (95% CI: 77.0%–95.0%) and LO-FTD of 75.7% (95% CI: 65.0%–86.0%). Estimating the contribution of genetics in FTD may help in driving future genetic studies to identify new pathogenetic determinants. We suggest that in most of the cases FTD is a genetic-based disease, even in the elderly. Different inheritance modality might be considered in future work, beyond autosomal dominant disease. Show more
Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, genetics, heritability, inheritance
DOI: 10.3233/JAD-130128
Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 371-376, 2014
