FATTORI DI RISCHIO GENETICI NELLA MALATTIA DI ALZHEIMER E NELLA DEMENZA FRONTOTEMPORALE: STUDIO DI ASSOCIAZIONE DI GENI CANDIDATI POSIZIONALI E FUNZIONALI

Alzheimer\u2019s disease (AD) and Frontotemporal Lobar Degeneration (FTLD) are two neurodegenerative and multifactorial diseases with complex etiology in which several genes involved in inflammation, oxidative damage and neuronal survival have been proposed to be candidate susceptibility factors. Given these premises, aims of this study have been to further analyze the association of candidate functional and positional genes in a population of 374 patient with AD, 291 with FTLD and 344 age matched controls. The first candidates studied have been the cell-dependent kinase inhibitor (CDKN) 2A and 2B, involved in cell cycle G1 phase progression, because abnormal cell cycle re-entry has been hypothesized to play a role in neurodegenerative disease, primarily AD. Allelic and genotypic frequencies of three tagging Single Nucleotide Polymorphisms (SNPs), namely rs3731239 T/C, rs2811710 C/T and rs3217992 G/A, spanning CDKN2A and CDKN2B, and covering 100% gene variability, were analyzed. According to our data, CDKN2A and CDKN2B don\u2019t likely act as risk factors for AD. Given the potential importance of kinesin KIF24, protein expressed in neurons and involved in axonal transport and neuron development, we studied the distribution of five Single Nucleotide Polymorphism (SNPs) located in the chromosome 9 haplotype identified via linkage analysis, including UBAP1 rs7018487, UBAP2 rs1785506 and rs307658, and KIF24 rs17350674 and rs10814083. A statistically significant increased frequency of the KIF24 rs17350674 AA genotype was observed in FTLD patients compared with controls, particularly in bvFTD and female patients, showing that KIF24 rs17350674 polymorphism may act as a risk factor for sporadic FTLD. BCL2-associated athanogene 1 (BAG1) is an anti-apoptotic factor interacting with tau and regulating its proteasomal degradation. A statistically significant decreased allelic frequency of the BAG-1 rs706118 SNP was observed in patients with FTLD, but not in AD. BAG-1 rs706118 SNP likely acts as protective factor for sporadic FTLD, but not for AD. Finally we studied the Heterogeneous nuclear ribonucleoprotein hnRNP-A1, which may be linked to AD, because it could influence the maturation of the Amyloid Precursor Protein (APP) mRNA, but also to FTLD, because it contains a glycine-rich consensus domain included in TAR DNA binding protein (TDP)43. In our study, hnRNP-A1 rs7967622 C/C genotype acts as risk factor only for FTLD in male population, while hnRNP-A1 relative expression levels were increased in AD patients, togheter with decreased levels of its transcription regulatory factor hsa-miR-590-3p. We confirmed the importance of genes influencing neuronal transport, metabolism and survival in both neurodegenerative diseases AD and FTLD; the observed differences are probably related to specific roles of these genes in pathogenic events occurring in FTLD only

CSF β-amyloid predicts prognosis in patients with multiple sclerosis

Background: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed. Objectives: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta 1\u201342 (A\u3b2) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages. Methods: Sixty patients were recruited and followed up for 3\u20135 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine A\u3b2 levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. Results: Lower CSF A\u3b2 levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = 120.65, p < 0.001). The multiple regression analysis confirmed CSF A\u3b2 concentration as a predictor of patients\u2019 EDSS increase (r = 120.59, p < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690\u20130.933, p = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed (p > 0.05). Conclusion: Low CSF A\u3b2 levels may represent a predictive biomarker of disease progression in MS

Balò’s concentric sclerosis : still to be considered as a variant of multiple sclerosis?

Bal\uf2\u2019s concentric sclerosis (BCS) is considered a rare demyelinating disease and regarded as an aggressive variant of multiple sclerosis (MS). We describe three cases (one male and two females) with neuroimaging features suggestive of BCS and heterogeneous symptoms, with benign long-term clinical course upon treatment with natalizumab and fingolimod. Neurological examination, blood and cerebrospinal fluid analyses, brain and spinal cord magnetic resonance imaging (MRI) and brain proton magnetic resonance spectroscopy were performed. At onset, patient #1 showed predominant cognitive impairment with consciousness disturbances; patient #2 presented with left hemiparesis; patient #3 demonstrated hesitance in speech and in written word production, along with right central facial palsy. All patients showed the typical MRI changes associated with BCS, such as concentric rings or a whorled appearance on T2-weighted and contrast-enhanced T1-weighted images. They were treated with high dosage i.v. steroid with clinical improvement and followed-up for 3\ua0years with different clinical course. Two patients fulfilled the revised McDonald criteria for MS and received preventive therapy, natalizumab and fingolimod, respectively, whereas the third patient is still stable without clinical and radiological evolution. All of them did not have new exacerbations or MRI lesions over 2\u20134\ua0year follow-up. Our descriptions demonstrate the heterogeneity of clinical presentation of BCS. Moreover, these case reports suggest that BCS may neither be rapidly progressive nor fatal and may be considered part of the MS spectrum. In line with this hypothesis, current treatments for MS were effective in our patients

CXCL10 haplotypes and multiple sclerosis : association and correlation with clinical course

CXCL10 (interferon-gamma-inducible protein-10) levels are increased in cerebrospinal fluid of multiple sclerosis (MS) patients with symptomatic attacks of inflammatory demyelination, supporting a role for this molecule in MS pathogenesis. Two hundred and twenty-six patients with MS and 235 controls were genotyped for G --> C and T --> C single nucleotide polymorphisms (SNPs) in exon 4 of CXCL10 gene. Haplotypes were tested for association and correlated with clinical variables. The two SNPs studied were in complete linkage disequilibrium. None of the determined haplotypes was associated with MS. However, carriers of the GGTT haplotype (defined as wild type, according to the sequence in National Centre for Biotechnology Information (NCBI) database) had a significantly lower progression index than non-carriers (P = 0.016). Furthermore, amongst patients who had an initial relapsing remitting (RR) course of the disease, the time between onset and second episode was significantly longer in GGTT carriers (P = 0.021). Considering secondary progressive (SP)-MS patients, the time between the initial RR form and the subsequent worsening to SP was longer in this group (P = 0.08). Therefore, the GGTT haplotype of the CXCL10 gene is not a susceptibility factor for the development of MS, but is probably to influence the course of MS, possibly contributing to slow down the progression of the disease

MDC/CCL22 intrathecal levels in patients with multiple sclerosis

MDC/CCL22 has been detected in the brain of mice with experimental autoimmune encephalomyelitis. MDC/CCL22 cerebrospinal fluid levels were evaluated in 56 patients with multiple sclerosis (MS) and in 17 controls. No significant differences were found, even when stratifying patients according to the disease subtype. Stratifying by gender, significantly increased MDC/CCL22 levels were observed in female patients when compared with female controls and male patients (109.03 versus 98.54 and 99.37 pg/mL, P 0.034 and 0.018, respectively). Therefore, MDC/CCL22 is likely to play a role in the development of MS in females only, possibly influencing the intracerebral recruitment of Th2 cells, which produce anti-inflammatory cytokines

CSF β-amyloid predicts early cerebellar atrophy and is associated with a poor prognosis in multiple sclerosis

BACKGROUND: Neurodegeneration is present from the earliest stages of multiple sclerosis (MS) and is critically involved in MS related clinical disability. Aim of the present study was to assess the connection between amyloid burden and early cerebellar grey matter (GM) atrophy compared to early brain GM atrophy in MS patients. METHODS: Forty newly diagnosed relapsing-remitting (RR-) MS patients were recruited. \u3b2-amyloid1-42 (A\u3b2) levels were determined in cerebrospinal fluid (CSF) samples from all subjects. All participants underwent neurological examination and brain magnetic resonance imaging (MRI) at baseline. Twenty-nine out of 40 patients repeated a brain MRI at 1-year follow-up. T1-weighted scans were segmented using the Voxel-Based Morphometry (VBM) protocol and the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). RESULTS: Between-group comparison of cerebellar parenchymal fraction (GM+WM/total cerebellar volume%) showed significant differences between A\u3b2high and A\u3b2low at baseline (p < 0.0001) and follow-up (p\u202f=\u202f0.02). Similarly, a between-group comparison of cerebellar GM fraction (GMF) showed significant differences between A\u3b2high and A\u3b2low at baseline (p\u202f=\u202f0.002) and follow-up (p\u202f=\u202f0.04). The multiple regression analysis showed CSF A\u3b2 concentration as the best predictor of GMF both at baseline and over time (\u3b2 = 0.505, \u3b2=0.377; p < 0.05). No significant results were found regarding global brain atrophy and CSF A\u3b2 concentration. CONCLUSIONS: Early cerebellar atrophy seems to be crucial in predicting a poor prognosis in MS, more than early global brain atrophy

IP-10 haplotypes and multiple sclerosis : association and correlation with clinical course

CXCL10 (interferon-gamma-inducible protein-10) levels are increased in cerebrospinal fluid of multiple sclerosis (MS) patients with symptomatic attacks of inflammatory demyelination, supporting a role for this molecule in MS pathogenesis. Two hundred and twenty-six patients with MS and 235 controls were genotyped for G --> C and T --> C single nucleotide polymorphisms (SNPs) in exon 4 of CXCL10 gene. Haplotypes were tested for association and correlated with clinical variables. The two SNPs studied were in complete linkage disequilibrium. None of the determined haplotypes was associated with MS. However, carriers of the GGTT haplotype (defined as wild type, according to the sequence in National Centre for Biotechnology Information (NCBI) database) had a significantly lower progression index than non-carriers (P = 0.016). Furthermore, amongst patients who had an initial relapsing remitting (RR) course of the disease, the time between onset and second episode was significantly longer in GGTT carriers (P = 0.021). Considering secondary progressive (SP)-MS patients, the time between the initial RR form and the subsequent worsening to SP was longer in this group (P = 0.08). Therefore, the GGTT haplotype of the CXCL10 gene is not a susceptibility factor for the development of MS, but is probably to influence the course of MS, possibly contributing to slow down the progression of the disease

IP-10 haplotypes and multiple sclerosis : association and correlation with clinical course

CXCL10 (interferon-gamma-inducible protein-10) levels are increased in cerebrospinal fluid of multiple sclerosis (MS) patients with symptomatic attacks of inflammatory demyelination, supporting a role for this molecule in MS pathogenesis. Two hundred and twenty-six patients with MS and 235 controls were genotyped for G --> C and T --> C single nucleotide polymorphisms (SNPs) in exon 4 of CXCL10 gene. Haplotypes were tested for association and correlated with clinical variables. The two SNPs studied were in complete linkage disequilibrium. None of the determined haplotypes was associated with MS. However, carriers of the GGTT haplotype (defined as wild type, according to the sequence in National Centre for Biotechnology Information (NCBI) database) had a significantly lower progression index than non-carriers (P = 0.016). Furthermore, amongst patients who had an initial relapsing remitting (RR) course of the disease, the time between onset and second episode was significantly longer in GGTT carriers (P = 0.021). Considering secondary progressive (SP)-MS patients, the time between the initial RR form and the subsequent worsening to SP was longer in this group (P = 0.08). Therefore, the GGTT haplotype of the CXCL10 gene is not a susceptibility factor for the development of MS, but is probably to influence the course of MS, possibly contributing to slow down the progression of the disease