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Ghidoni R.,Proteomics Unit | Ghidoni R.,Irccs Centro S Giovanni Of Dio Fbf | Benussi L.,Irccs Centro S Giovanni Of Dio Fbf | Glionna M.,Irccs Centro S Giovanni Of Dio Fbf | And 6 more authors.
Journal of Alzheimer's Disease | Year: 2010

Recent years have witnessed an increasing interest in mild cognitive impairment (MCI), particularly as a possible prodromal stage of Alzheimer's disease (AD). Experimental and clinical data have suggested that cystatin C (CysC) is protective against the development of AD. In this study, we sought to cross-sectionally and longitudinally investigate the changes in plasma CysC levels in patients with MCI and whether the levels of this molecule might serve as a biochemical predictor of cognitive decline in this patient group. Cross-sectional analysis of baseline data showed a borderline significant difference in plasma CysC levels among the three study groups (Controls, n=63; AD, n=63; MCI, n=59) (p =0.032) that disappeared after post hoc analysis. Plasma CysC levels did not differ at baseline (t1) and at follow-up (t2) both in MCI patients that converted to AD (n= 32) and those that did not convert (n=27). However, a significant independent association between CysC at t1 and CysC at t2 was found in non-converters but not in converters MCI subjects. Moreover, when disease onset was evaluated in patients groups stratified on the basis of their CysC plasma levels, a significant anticipation of the conversion to dementia in MCI subjects with CysC levels below the median (CysC < 1067 ng/ml) (p =0.0011) was observed. Altogether, this work adds to the growing body of literature suggesting that CysC modulates the clinical expression of cognitive decline, and opens a new area of investigation of CysC as a therapeutic target for neurodegenerative disorders. © 2010 IOS Press and the authors. All rights reserved.

Tangaro S.,National Institute of Nuclear Physics, Italy | Amoroso N.,National Institute of Nuclear Physics, Italy | Amoroso N.,University of Bari | Boccardi M.,Irccs Centro S Giovanni Of Dio Fbf | And 11 more authors.
Physica Medica | Year: 2014

The hippocampus is an important structural biomarker for Alzheimer's disease (AD) and has a primary role in the pathogenesis of other neurological and psychiatric diseases. This study presents a fully automated pattern recognition system for an accurate and reproducible segmentation of the hippocampus in structural Magnetic Resonance Imaging (MRI). The method was validated on a mixed cohort of 56 T1-weighted structural brain images, and consists of three processing levels: (a) Linear registration: all brain images were registered to a standard template and an automated method was applied to capture the global shape of the hippocampus. (b) Feature extraction: all voxels included in the previously selected volume were characterized by 315 features computed from local information. (c) Voxel classification: a Random Forest algorithm was used to classify voxels as belonging or not belonging to the hippocampus. In order to improve the classification performance, an adaptive learning method based on the use of the Pearson's correlation coefficient was developed. The segmentation results (Dice similarity index=0.81±0.03) compare well with other state-of-the art approaches. A validation study was conducted on an independent dataset of 100 T1-weighted brain images, achieving significantly better results than those obtained with FreeSurfer. © 2014 Associazione Italiana di Fisica Medica.

Villa C.,University of Milan | Ghezzi L.,University of Milan | Pietroboni A.M.,University of Milan | Fenoglio C.,University of Milan | And 18 more authors.
Journal of Alzheimer's Disease | Year: 2011

A number of mutations in microtubule associated protein tau gene (MAPT), causing frontotemporal lobar degeneration (FTLD) with tau pathology, are located in the four-repeated microtubule (MT) binding domains and affect the ability of tau to bind MTs. Here, we describe a novel variant lying in the second MT domain, found in a female patient diagnosed clinically with progressive nonfluent aphasia (PNFA), with a positive family history for dementia. At 65 years, she started developing progressive language deficits, characterized by expression difficulties and word coordination impairment. She came to our attention at 67 years. Her MMSE score was 22/30. A Brain CT scan showed mild diffuse cortical atrophy, ventricles' asymmetry (left > right), and very mild signs of chronic vasculopathy. Cerebrospinal fluid analysis showed normal amyloid-β 42, tau, and P-tau levels. She was diagnosed with PNFA according to current diagnostic criteria. A novel exon 10 MAPT variant was identified (g.123798G > A), which leads to an amino acidic change (p.Gly304Ser) in the second MT microtubule binding domain. In silico analysis predicted that this variant is damaging on protein structure and function. Additional 168 FTLD patients and 503 controls screened (1342 chromosomes) did not carry the variant, suggesting that it is a mutation rather than a polymorphism. The amino acid change likely compromises the ability of tau to properly regulate the dynamic behavior of microtubules. © 2011-IOS Press and the authors. All rights reserved.

Cantoni C.,University of Milan | Fenoglio C.,University of Milan | Cortini F.,University of Milan | Venturelli E.,University of Milan | And 18 more authors.
Journal of Alzheimer's Disease | Year: 2010

Two hundred and fifty one Italian patients with sporadic frontotemporal lobar degeneration (FTLD) and 259 age-matched controls were tested for association with the tagging single nucleotide polymorphisms (SNPs) rs741810 and rs1052352 in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS). Only patients negative for GRN mutations were included. Considering each SNP alone, no differences in either allelic or genotypic frequencies between patients and controls were found (P > 0.05), even stratifying according to gender or the presence of concomitant motor neuron disease. Haplotype analysis failed to detect haplotypes associated with FTLD. According to these results, FUS/TLS is not a susceptibility factor for the development of sporadic FTLD. © 2010-IOS Press and the authors. All rights reserved.

Benussi L.,Irccs Centro S Giovanni Of Dio Fbf | Ghidoni R.,Irccs Centro S Giovanni Of Dio Fbf | Ghidoni R.,Proteomics Unit | Galimberti D.,University of Milan | And 5 more authors.
European Journal of Neurology | Year: 2010

Background and purpose: Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementia. Given the role of cystatin C in brain neurodegeneration and neuroregeneration, the aim of this study was to determine whether the cystatin C gene (CST3) was genetically associated with FTLD. Methods: Hundred and eighty-six FTLD patients and 457 controls underwent CST3 analysis by PCR and KspI enzyme digestion. Results: In FTLD patients negative for the presence of PGRN mutations, we found an over-representation of the CST3 haplotype B [odds ratio (OR = 1.619, P = 0.002)] and of AB/BB genotypes (OR = 1.704, P = 0.008) in FTLD patients. Conclusions: The present study indicated the CST3 B haplotype as a putative risk factor for FTLD in PGRN mutations negative patients. The reduced level of cystatin C, previously associated with the B haplotype, might represent the molecular factor responsible for the increased risk. Long-term depletion of neurotrophic factors, such as cystatin C and progranulin proteins, seem to be a common theme in FTLD: boosting the expression of such proteins might be a promising therapeutic strategy for FTLD. © 2009 EFNS.

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