We prospectively assessed the influence of JCV- status on disability’s accrual in RRMS patients treated with Natalizumab at two tertiary MS centres, settled in Italy.

Increased levels of alpha-1-antichymotrypsin (ACT), a protease inhibitor and an acute phase protein, have been found in the brain and peripheral blood of patients with Alzheimer’s disease (AD). Patients from northern Italy with a clinical diagnosis of probable AD, and patients with early onset AD (EOAD) from UK with AD neuropathological diagnosis were genotyped for a new polymorphism in the promoter region of the ACT gene which has been shown to affect ACT expression. A subset of patients with clinical AD from northern Italy was also followed up for 2 years and monitored for cognitive decline. The ACT TT promoter genotype was associated with an increased risk of EOAD independently from the presence of the apolipoprotein E (APOE) ε 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele ε 4. The ACT gene appears to influence the early clinical development of the disease, and the interaction of the ACT and APOE genes affects clinical progression of AD.

In a group of 299 migraine patients and 306 control subjects, the association of the -308 G/A polymorphism in the tumor necrosis factor-alpha gene (TNFalpha) with the occurrence and clinical characteristics of migraine was tested. Homozygosity for the G allele was associated with an increased risk of migraine (odds ratio [OR] = 2.85, p < 0.001). When the patients were divided into subgroups, the association was confirmed in patients affected by migraine without aura (OR = 3.30, p < 0.001) but not in migraine with aura. These data suggest that the TNFalpha gene or a linked locus significantly modulates the risk for migraine.

Two different polymorphic regions of the interleukin-6 (IL-6) gene were investigated in patients with Alzheimer’s disease (AD) and non-demented controls. The −174 C allele in the promoter region of IL-6 gene was over-represented in AD patients compared to controls and significantly increased the risk of AD. Moreover, the −174 CC genotype was associated with a high risk of the disease in women. The D allele of a variable number of tandem repeat (VNTR) was in strong linkage disequilibrium with the −174 C allele and slightly increased AD risk. On the other hand, the frequency of the VNTR C allele was decreased in patients with AD and was negatively associated with the risk of developing AD. Both the −174 CC and VNTR DD genotypes were also associated with increased IL-6 levels in the blood and brain from AD. These findings suggest that IL-6 may play a multifaceted role in AD by affecting the turnover of the cytokine.

Interleukin-1 (IL-1) gene polymorphisms are associated with an increased risk of Alzheimer’s disease (AD) and it has been suggested that altered immune responses of the brain may play a role in the pathogenesis of the disease. Here we investigated whether IL-1β polymorphisms affected neuro-pathological features and clinical status of AD patients with autopsy confirmed diagnosis of the disease. AD patients (n=133) were genotyped for the polymorphic regions in the apolipoprotein E ε (APOE ε) and interleukin-1β (IL-1β)) genes. APOE ε4 carriers showed increased neuritic amyloid plaques (NP) and neurofibrillary tangles (NFT). The IL-1β +3953 polymorphism influenced survival in AD patients and those with the TT genotype and without the APOE ε4 allele showed the shortest cumulative survival. Patients with the +3953 IL-1β T and without the APOE ε4 alleles had reduced NP and NFT, a delayed ages at onset and death, but a decreased duration of the disease. On the other hand a different polymorphism of the IL-1β gene at position −511 did not influence any AD features. Our findings suggest that IL-1β gene by affecting brain immune responses may influence the age at onset of the disease, survival and AD progression.

To assess the role of interleukin-6 (IL-6) in migraine, we analyzed the -174 G/C IL-6 gene polymorphism in 268 patients with migraine and 305 controls. No significant difference in the distribution of IL-6 genotypes (chi(2)=0.601, P=0.74) and allelic frequencies (chi(2)=0.024, P=0.876) was found. When patients were subdivided into subgroups (migraine with aura, migraine without aura and mixed headaches), IL-6 alleles were similarly distributed. Comparison of the clinical features of the disease with the -174 G/C IL-6 genotypes showed no significant difference. In conclusion, we found no significant association between the -174 G/C IL-6 polymorphism and the occurrence or the clinical features of migraine.

We amplified sequences of the Chlamydia pneumoniae (CP) major-outer membrane protein in the cerebrospinal fluid (CSF) from 23 of 107 (21.5%) relapsing-remitting or secondary progressive multiple sclerosis (MS) patients and two of 77 (2.6%) patients with other neurological diseases (OND) (P = 0.00022). CP+ patients showed magnetic resonance imaging (MRI) evidence of more active disease (P = 0.02) compared to CP- MS patients and tended to have an anticipation of age at disease onset (32.3 +/- 12 versus 28.5 +/- 10 years; P = ns) causing a longer disease duration (7.5 +/- 5 versus 4.4 +/- 4 years; P = 0.016) at the time of clinical evaluation. These findings, although indirectly, suggest that CP infection of the central nervous system (CNS) might affect disease course in a subgroup of MS patients.

Interleukin-1α (IL-1α) and IL-1β are two pro-inflammatory cytokines involved in the pathogenesis of Alzheimer’s disease (AD). The genes coding for IL-1α (IL-1A) and for IL-1β (IL-1B) are clustered in chromosome 2q14–2q14.2. In a previous work, we investigated the role of IL-1A promoter polymorphism (−889 position) in AD pathogenesis: IL-1A −889 TT genotype was associated with sporadic early onset AD. We now report the study on polymorphism of exon 5 IL-1B in position +3953, the nearest polymorphism to −889 IL-1A. We found that the genotype distribution of IL-1B +3953 varied significantly between patients with early and late onset of AD (P<0.0001). Patients carrying IL-1B +3953 CT or TT genotypes had 4 or 5 years anticipation of AD onset (P=0.0034; odds ratio for early onset, 3.01) and 7 years anticipation if they also carried the IL-1A −889 TT genotype (P<0.0001; odds ratio for early onset, 7.4). These data further support a role for inflammation-related genes in AD or indicate linkage disequilibrium with an unknown chromosome 2 locus.

Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for Alzheimer's disease (AD). We analyzed single-nucleotide polymorphisms in 10 glucocorticoid-related genes in a population of 814 AD patients and unrelated control subjects. Set-association analysis revealed that a rare haplotype in the 5' regulatory region of the gene encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) was associated with a 6-fold increased risk for sporadic AD. Results of a reporter-gene assay indicated that the rare risk-associated haplotype altered HSD11B1 transcription. HSD11B1 controls tissue levels of biologically active glucocorticoids and thereby influences neuronal vulnerability. Our results indicate that a functional variation in the glucocorticoid system increases the risk for AD, which may have important implications for the diagnosis and treatment of this disease.

Tissue inhibitor of metalloproteinases I (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-I levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD. (C) 2002 Lippincott Williams Wilkins.

To investigate the role of apolipoprotein E (APOE) polymorphisms in migraine, we analyzed the APOE genotypes of 241 migraine patients and 587 controls. The results of a Chi-square analysis indicated that APOE alleles were similarly distributed (chi(2)=2.89, P=0.24) between cases and controls. However, we found a significant (P<0.001) increase of the varepsilon2-varepsilon4 genotype in the group of migraine patients. Patients were divided into three subgroups: migraine with aura; migraine without aura; and mixed headaches (migraine associated with tension-type headache). Subgroup analysis showed that the varepsilon2-varepsilon4 genotype was significantly increased only in patients with mixed headaches. The stratification of patients by APOE status did not reveal significant associations with the clinical features of the disease. In conclusion, we observed no significant association between APOE polymorphisms and migraine. The association between the APOE varepsilon2-varepsilon4 genotype and the tension-type headache deserves further evaluation.

Myasthenia gravis (MG) is a multifactorial autoimmune disease of the neuromuscular junction. We investigated the relation between four polymorphisms of the interleukin (IL)-1 gene cluster on 2q12-22, and MG susceptibility and clinical features in a large cohort of individuals. No polymorphism was associated with MG susceptibility. However, the IL-1A -889 CC genotype was associated with early disease onset (p=0.0044) in the whole MG group and the subgroup of CC males developed MG about 18 years earlier than males carrying other IL-1A -889 genotypes (p=0.022). This finding suggests that IL-1A is a disease modifier in MG, or is in linkage disequilibrium with an unknown locus on chromosome 2.

Several studies have described polymorphisms in the genes encoding interleukin-1α (IL-1α) and IL-1β cytokines and their implication in the onset of Alzheimer disease or in linkage disequilibrium with an as yet to be identified second locus on chromosome 2. However, these results have been associated with the sporadic forms of Alzheimer disease. Here we present data on the effects of the interleukin 1-β exonic polymorphism (+3953) using a series of cohort healthy control samples and in vitro protein secretion assays.

Twenty years after a first survey, a follow-up study was performed on the prevalence of MS in Enna (Sicily), southern Italy. The prevalence of definite MS rose from 53 to 120.2 per 100,000 population. The incidence of definite MS for the period 1986 to 1995 was 5.7 per 100,000 per year. The innermost part of Sicily shows an elevated prevalence of MS, second only to Sardinia in the Mediterranean area.

Although its main biological function is still unknown, the prion protein is involved in normal synaptic function.1Interestingly, the presence of a valine (V), replacing a methionine (M) at codon 129 of the prion protein gene (PRNP), has been associated with poor performance in cognitive tests in a large cohort of aged, non-demented, French people.2 Accordingly, this polymorphic gene represents a suitable candidate for an association with Alzheimer's disease, a dementing disorder characterised by neuronal degeneration and synaptic loss. To assess whether the PRNP V/M codon129 polymorphism—alone or in combination with polymorphisms in the apolipoprotein (APO)E3 and interleukin (IL)-1α4 genes, already shown to be associated with Alzheimer's disease—affects the occurrence or clinical features of the disease, we performed a case-control study in a cohort of Italian patients with sporadic Alzheimer's disease and age matched healthy controls. Venous blood was collected from 212 Italian patients (130 women, 82 men; mean (SD) age at disease onset 68.3 (8.0) years) affected by clinically probable Alzheimer's disease, according to McKhann's criteria. Patients were also divided into those with early disease onset (⩽65 years; 72 patients; mean (SD) age at disease onset 57.0 (7.5) years), and those with a late onset (>65 years; 140 patients; mean (SD) age …

Genetic polymorphisms of immunorelevant genes may modulate occurrence or clinical features of multifactorial diseases. PECAM-1 is an adhesion molecule crucial for transmigration of cells from blood to tissues, but its genetic contribution to multifactorial diseases has never been investigated. We have identified and characterized a tetranucleotide repeat polymorphism within the third intron of PECAM-1. In a cohort of healthy controls (HC), we found 10 alleles. An assessment of the association of this polymorphism with multiple sclerosis (MS) showed similar allele and genotype frequencies in HC and MS patients as well as in MS patients differing for the gravity of their disease course. We conclude that although potentially able to affect organ-specific autoimmune diseases, this new PECAM-1 polymorphism, does not seem to contribute to the genetic background of MS.