Alzheimer Disease: Bresolin N

Scarpini E, Galimberti D, Guidi I, Bresolin N, Scheltens P. · Dept. of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy. · J Neurol Sci. · Pubmed #16249006 No free full text.

Abstract: Language disturbances are common features occurring in different neurodegenerative diseases, including Alzheimer's disease (AD) and the Frontotemporal Lobar Degeneration (FTLD) variants Primary Progressive Aphasia (PPA) and Semantic Dementia (SD). Despite AD and FTLD are supposed to have a different pathophysiology, PPA has been demonstrated to have in some cases an AD pathological component. The syndromic and etiological heterogeneity is crucial for the differential diagnosis and consequently for a therapeutical approach. Here, the case of a patient with progressive isolated language disturbances is presented, and further discussed on the basis of current diagnostic criteria and available guidelines for treatment.

Guidi I, Galimberti D, Venturelli E, Lovati C, Del Bo R, Fenoglio C, Gatti A, Dominici R, Galbiati S, Virgilio R, Pomati S, Comi GP, Mariani C, Forloni G, Bresolin N, Scarpini E. · Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. · Neurobiol Aging. · Pubmed #15718036 No free full text.

Abstract: The distribution of the Glu298Asp polymorphism in NOS3 gene was determined in 405 Italian patients with "probable" Alzheimer's disease (AD) compared with 253 age-matched controls. Total plasma homocysteine (tHcy) levels were evaluated in 97 patients and 23 controls, and were correlated with the Glu298Asp genotype. A significantly increased frequency of the Glu/Glu genotype in late onset AD (LOAD) patients was found. tHcy levels were significantly increased in patients compared with controls and, notably, higher in LOAD than in early onset AD (EOAD). Stratifying by the Glu298Asp genotype, a trend toward an increase of tHcy was present in Glu/Glu homozygous. This wild type genotype seems to be associated with LOAD. tHcy levels are significantly increased in AD compared with controls and, moreover, higher in LOAD than in EOAD, possibly in correlation with the microvascular disease occurring with aging. Besides, a contribution of the Glu/Glu genotype in increasing tHcy levels has been observed.

Cortini F, Fenoglio C, Guidi I, Venturelli E, Pomati S, Marcone A, Scalabrini D, Villa C, Clerici F, Dalla Valle E, Mariani C, Cappa S, Bresolin N, Scarpini E, Galimberti D. · Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy. · Eur J Neurol. · Pubmed #18752597 No free full text.

Abstract: BACKGROUND AND PURPOSE: Progranulin (PGRN) expression is increased in activated microglia in Alzheimer's disease (AD) brain, suggesting a potential role in this pathology. METHODS: A mutation scanning of exons and flanking regions of PGRN was carried out in 120 patients with sporadic frontotemporal lobar degeneration and 145 with sporadic AD. RESULTS: Amongst variants not yet deposited, a novel allelic variant was identified in Exon 1 (g100169G > A). It leads to an amino acidic change (p.Gly35Arg) and was observed in a patient with late onset AD. In silico analysis predicted that this mutation is possibly damaging. A second variant (g.100165C > T), resulting in a silent mutation (pAsp33Asp), was found in a patient with semantic dementia and in another with early onset AD. Both variants were absent in 226 controls. In addition, two rare non-pathogenic variants lying very close to PGRN splice-site regions (IVS2 + 7-->G > A and IVS7 + 7-->G > A) were observed. Transcriptional analysis in peripheral blood mononuclear cells from patients demonstrated they do not affect exon splicing. CONCLUSIONS: A novel putative PGRN mutation leading to an amino acidic substitution was identified in a patient with clinical AD.

Galimberti D, Venturelli E, Fenoglio C, Guidi I, Villa C, Bergamaschini L, Cortini F, Scalabrini D, Baron P, Vergani C, Bresolin N, Scarpini E. · Dept. of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. · J Neurol. · Pubmed #18204920 No free full text.

Abstract: Cerebrospinal fluid (CSF) levels of interleukin (IL)-6, IL-11 and leukaemia inhibitory factor (LIF) were evaluated in 43 patients with Alzheimer's disease (AD) and 24 patients with frontotemporal lobar degeneration (FTLD) as compared with 30 agematched controls (CON), and correlated with clinical and demographic data and with CSF biomarkers amyloid beta (A beta)42, total tau and tau phosphorylated at position 181 (P-tau). CSF IL-11 mean levels were significantly increased in AD and FTLD as compared with CON (6.5 +/- 4.6 and 6.6 +/- 5.1 versus 3.1 +/- 3.3 pg/ml, P = 0.009). IL-6 mean levels did not differ between patients and CON (P > 0.05),whereas LIF levels were not detectable in patients or in CON. In AD patients, a significantly positive correlation between MMSE scores and IL-11 CSF concentration was observed (r = 0.344, P = 0.028). No correlations with CSF A beta 42, total tau and P-tau were found. IL-11, but not IL-6 levels are increased in AD and FTLD, and the highest peaks were observed in patients with a less severe degree of cognitive deterioration, therefore suggesting a role of this cytokine in early phases of neurodegeneration.

Galimberti D, Scarpini E, Venturelli E, Strobel A, Herterich S, Fenoglio C, Guidi I, Scalabrini D, Cortini F, Bresolin N, Lesch KP, Reif A. · Department of Neurological Sciences, Dino Ferrari Center, University of Milan, Fondazione Ospedale Maggiore Policlinico IRCCS, Milan, Italy. · Neurobiol Aging. · Pubmed #17418914 No free full text.

Abstract: The gene encoding NOS-I (NOS1) displays a complex transcriptional regulation, with nine alternative first exons. Exon 1c and 1f are the most abundant forms in the brain. A functional single nucleotide polymorphism (SNP) in exon 1c and a polymorphism in exon 1f, consisting of a variable number of tandem repeats (VNTR) originating short (S) and long (L) alleles, were studied in 184 patients with Alzheimer's disease (AD) and 144 gender- and age-matched controls. No differences were found for the Ex1c G-84A. The Ex1f-VNTR S allele was significantly more common in AD (55% versus 44%, P=0.009, OR=1.52) as was the S/S genotype (28% versus 14%, P=0.008; OR=2.37). The S allele showed a highly significant interaction with the ApoE epsilon 4 allele (OR: 10.83). Therefore, short alleles of the NOS1 exon 1f-VNTR are likely to be susceptibility factors for AD, and interact with the epsilon 4 allele to markedly increase the AD risk.

Fenoglio C, Galimberti D, Piccio L, Scalabrini D, Panina P, Buonsanti C, Venturelli E, Lovati C, Forloni G, Mariani C, Bresolin N, Scarpini E. · Department of Neurological Sciences, "Dino Ferrari" Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy. · Neurosci Lett. · Pubmed #17088018 No free full text.

Abstract: Triggering Receptor Expressed on Myeloid cells (TREM)2 deficiency originates a genetic syndrome characterized by bone cysts and presenile dementia, named Nasu-Hakola disease (NHD). Early onset dementia and marked involvement of frontal regions are features characterizing both NHD and other kinds of neurodegenerative disorders, such as Frontotemporal Lobar Degeneration (FTLD), and, in some cases, Alzheimer's disease (AD). Three Single Nucleotide Polymorphisms (SNPs) in TREM2 coding region were screened by allelic discrimination in a population of probable AD patients as well as FTLD patients as compared with age-matched controls. In addition, mutation scanning of the coding region of TREM2 gene was carried out in 7 patients with early onset AD (EOAD), 16 FTLD, and 20 controls. None of the SNPs analyzed was present, either in patients or controls. Moreover, mutation scanning of the five exons of TREM2 failed to detect the presence of novel polymorphisms. These data demonstrate that TREM2 coding region is highly conserved, implying a crucial role of this receptor. Further studies, including a functional analysis, are certainly required to clarify the role of TREM2 in neurodegenerative processes.

Venturelli E, Galimberti D, Fenoglio C, Lovati C, Finazzi D, Guidi I, Corrà B, Scalabrini D, Clerici F, Mariani C, Forloni G, Bresolin N, Scarpini E. · Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Italy. · Neurosci Lett. · Pubmed #16787707 No free full text.

Abstract: Interferon-gamma-inducible Protein-10 (IP-10) is supposed to play a role in Alzheimer's disease (AD) development, as demonstrated by increased levels in cerebrospinal fluid from patients with AD. A mutation scanning of IP-10 exonic region was carried out in 10 patients with AD and 10 age-matched controls, demonstrating the presence of two previously reported single nucleotide polymorphisms (SNPs) in exon 4 (G-->C and T-->C) as well as a novel SNP in exon 2 (C-->T). Exon 4 G-->C and T-->C allelic variants were next evaluated in a population of 279 AD patients and 251 controls, in order to determine whether their presence could influence the susceptibility towards the development of the disease. These two SNPs were in complete linkage disequilibrium. No differences in haplotype frequencies were found in AD patients as compared with controls, even stratifying according to the presence of Apolipoprotein E varepsilon4 allele, gender or age at onset. A new protocol was developed to easily determine the C-->T SNP in exon 2. A preliminary analysis revealed a very low frequency of this allelic variant (1%). Therefore, the complete association study was not carried out because the size of our population was not sufficient to draw reliable conclusions. According to these results, IP-10 does not seem to be a risk factor for AD. However, a novel rare polymorphism has been identified, which could exert a role in AD susceptibility. Thus, further studies on larger populations are needed before confidently excluding IP-10 as a susceptibility gene for AD.

Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, Guidi I, Blankenstein MA, Bresolin N, Scarpini E. · Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. · Arch Neurol. · Pubmed #16606766 links to  free full text

Abstract: BACKGROUND: Immunoreactivity for several chemokines and for their related receptors has been demonstrated in resident cells of the central nervous system, and the up-regulation of some of them is associated with pathological changes found in Alzheimer disease (AD). OBJECTIVE: To determine interferon-gamma-inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), and interleukin 8 (IL-8) levels in cerebrospinal fluid (CSF) from subjects with amnestic mild cognitive impairment (MCI) and patients with AD as compared with age-matched controls. PATIENTS: Thirty-eight subjects with amnestic MCI, 36 patients with AD, and 41 age-matched subjects with noninflammatory affections of the nervous system. DESIGN: Evaluation of CSF chemokine production at time of diagnosis of MCI and AD; correlation with clinical and personal data. Longitudinal evaluation of subjects with MCI until conversion to AD. RESULTS: Cerebrospinal fluid IP-10 concentration was significantly increased in patients with MCI and mild AD but not in patients with severe AD (Mini-Mental State Examination score <15), whereas MCP-1 and IL-8 levels were increased in patients with MCI and all patients with AD. A significant positive correlation between Mini-Mental State Examination score and CSF IP-10 or MCP-1 concentration was observed in patients with AD. No correlation between IP-10 levels and age was found, whereas MCP-1 and IL-8 levels correlated positively with age. Out of 38 subjects with MCI, 19 developed AD within a 1- to 3-year follow-up. CONCLUSIONS: The presence of inflammatory molecules is likely to be a very early event in AD pathogenesis, even preceding the clinical onset of the disease, as demonstrated by subjects with MCI who developed AD over time. Interferon-gamma-inducible protein 10 is specifically increased in MCI and seems to decrease with the progression of AD, whereas MCP-1 and IL-8 are up-regulated also in late stages of the disease, suggesting a role in phases in which neurodegeneration is prevalent.

Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Venturelli E, Pijnenburg YA, Bresolin N, Scarpini E. · Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy. · Neurology. · Pubmed #16401871 No free full text.

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Guidi I, Galimberti D, Lonati S, Novembrino C, Bamonti F, Tiriticco M, Fenoglio C, Venturelli E, Baron P, Bresolin N, Scarpini E. · Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. · Neurobiol Aging. · Pubmed #16399211 No free full text.

Abstract: Increasing evidence supports a role of oxidative imbalance, characterized by impaired antioxidant enzymatic activity and increased reactive oxygen species (ROS) production, in mild cognitive impairment (MCI) and Alzheimer's disease (AD) pathogenesis. Hyperhomocysteinemia, another risk factor for AD, also contributes to oxidative damage. Plasma total homocysteine (tHcy) and ROS levels, and total antioxidant capacity (TAC) were determined in 71 AD, 36 MCI and 28 vascular dementia (VaD) patients as well as in 44 age-matched controls. tHcy levels were significantly increased in patients with AD and VaD an a trend towards an increase in multiple domain MCI was observed. TAC was significantly decreased in AD as well as MCI, but not in VaD patients. In AD patients, a negative correlation was found between TAC and disease duration. ROS levels did not differ among groups, but were correlated with age. In conclusion, a pattern characterized by increased tHcy levels and decreased TAC is present in AD as well as MCI patients. While increased tHcy levels were also found in VaD, TAC modifications occur specifically in AD. ROS levels appear to be correlated with age rather than with a specific dementing disorder, thus leading to the hypothesis that oxidative imbalance observed in AD could be due to a decreased TAC.

Galimberti D, Fenoglio C, Lovati C, Venturelli E, Guidi I, Corrà B, Scalabrini D, Clerici F, Mariani C, Bresolin N, Scarpini E. · Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. <> · Neurobiol Aging. · Pubmed #16307829 No free full text.

Abstract: Upregulation of a number of chemokines, including monocyte chemotactic protein-1 (MCP-1), is associated with Alzheimer's disease (AD) pathological changes. Emerging evidence suggests that inflammatory events precede the clinical development of AD, as cytokine disregulation has been observed also in patients with mild cognitive impairment (MCI). MCP-1 levels were evaluated in serum samples from 48 subjects with MCI, 94 AD patients and 24 age-matched controls. Significantly increased MCP-1 levels were found in MCI and mild AD, but not in severe AD patients as compared with controls. mRNA levels in peripheral blood mononuclear cells (PBMC), evaluated by quantitative RT-PCR analysis, paralleled serum MCP-1 levels. Moreover, a progressive MCP-1 decrease was observed over a 1-year follow up in a subgroup of MCI subjects converted to AD. MCP-1 upregulation is likely to be a very early event in AD pathogenesis, by far preceding the clinical onset of the disease. Nevertheless, as MCP-1 is likely to play a role in several pathologies with an inflammatory component, a possible usefulness as an early AD biomarker would be possible only in combination with other molecules.

Del Bo R, Scarlato M, Ghezzi S, Martinelli-Boneschi F, Fenoglio C, Galimberti G, Galbiati S, Virgilio R, Galimberti D, Ferrarese C, Scarpini E, Bresolin N, Comi GP. · Dino Ferrari Centre, Department of Neurological Sciences, University of Milan and Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Padiglione Ponti, Milano, Italy. · Neurobiol Aging. · Pubmed #16099550 No free full text.

Abstract: The methionine/valine (M/V) polymorphism at codon 129 within the prion protein gene (PRNP) represents a known risk factor for Creutzfeldt-Jakob disease (CJD). Few authors reported also the effects of this polymorphism on the risk of Alzheimer's disease (AD), although with controversial results. To better clarify this issue, we performed a novel case-control study and a meta-analysis of published association studies between PRNP and AD. Our findings argue against PRNP as a susceptibility gene for developing AD in the Italian population but support the hypothesis that the V allele influences cognitive performances. The meta-analysis, revealed that Caucasian subjects homozygous at codon 129 had a 1.3-fold increased risk [95% CI: 1.0-1.6, p = 0.05] of developing AD compared to heterozygous individuals. We also observed that MM genotype and M allele represent a risk factor for AD, independently from the ethnic background, providing a significant but modest association between this polymorphism and AD.

Venturelli E, Galimberti D, Lovati C, Fenoglio C, Scalabrini D, Mariani C, Forloni G, Bresolin N, Scarpini E. · Department of Neurological Sciences, "Dino Ferrari" Center and CEND, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy. · Neurosci Lett. · Pubmed #15925107 No free full text.

Abstract: A common single nucleotide polymorphism (SNP), consisting in a T-->C transition (T-786C) in endothelial nitric oxide synthase (NOS3), has been reported to be associated with vascular pathologies, but no information are available on a possible association with AD. T-786C genotype was determined by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) assay in an Italian population of 432 AD patients compared with 360 healthy controls, matched for ethnic background, age and gender. Peripheral blood mononuclear cells (PBMC) from 22 subjects (11 AD and 11 controls) carrying different genotypes were isolated. Total RNA was extracted and analyzed by real-time PCR. No significant differences either in allelic or genotypic frequencies of the T-786C polymorphism between AD and normal population were observed, even stratifying AD patients by age at onset, gender, or ApoE status. However, expression of NOS3 in PBMC seems to be influenced by the presence of the C mutated allele, as demonstrated by a tendency towards a decrease in mRNA levels in C carriers, assessed by real-time PCR assay. This effect was observed both in patients and controls, independently from the cognitive impairment, and is likely to be dose-dependent, being mostly evident in CC homozygous. In conclusion, the T-786C SNP does not seem to be a risk factor for sporadic AD, but its presence correlates with a trend toward lower NOS3 expression rate, possibly exerting a beneficial effect in AD by contributing to lower oxidative damage.

Galimberti D, Venturelli E, Gatti A, Lovati C, Fenoglio C, Mariani C, Forloni G, Bresolin N, Scarpini E. · No affiliation provided · J Neurol. · Pubmed #15765269 No free full text.

This publication has no abstract.

Del Bo R, Scarlato M, Ghezzi S, Martinelli Boneschi F, Fenoglio C, Galbiati S, Virgilio R, Galimberti D, Galimberti G, Crimi M, Ferrarese C, Scarpini E, Bresolin N, Comi GP. · Department of Neurological Sciences, Dino Ferrari Centre and Centre of Excellence on Neurodegenerative Diseases, University of Milan, I.R.C.C.S. Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. · Ann Neurol. · Pubmed #15732116 No free full text.

Abstract: Converging evidence points to a pivotal role of vascular endothelial growth factor (VEGF) in neuronal protection and a lack of its activity in neurodegenerative disorders. To investigate this possible association, we screened the VEGF gene promoter for various well-known single-nucleotide polymorphisms in a series of 249 consecutively recruited Italian patients with sporadic Alzheimer's disease (AD). Genetic analysis indicated different distributions of two single-nucleotide polymorphisms in the AD population compared with healthy control subjects. In particular, the frequencies of -2578A/A and -1198C/T genotypes were significantly greater in AD patients than in control subjects (23.7 vs 14.7% and 2.8 vs 0%, respectively). The -2578A/A genotype was associated with an increased risk for disease, independently of apolipoprotein E genotype. The risk was significantly increased with respect to various VEGF genotype combinations. In contrast, no difference in serum VEGF levels was detected comparing 96 patients and 49 control subjects. These findings suggest that polymorphisms within the promoter region of the VEGF gene confer greater risk for AD, probably by reducing its neuroprotective effect, and confirm the biological role of VEGF in neurodegenerative processes.

Galimberti D, Fenoglio C, Lovati C, Gatti A, Guidi I, Venturelli E, Cutter GR, Mariani C, Forloni G, Pettenati C, Baron P, Conti G, Bresolin N, Scarpini E. · Department of Neurological Sciences, "Dino Ferrari" Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. · J Neurol Sci. · Pubmed #15465089 No free full text.

Abstract: Monocyte chemoattractant protein-1 (MCP-1) and RANTES, as well as their related receptors, have been shown to be involved in Alzheimer's disease (AD) pathogenesis. Genes for their related receptors, CCR2 and CCR5, respectively, are characterized by the presence of two polymorphisms: a conservative change of a valine with an isoleucine at codon 64 of CCR2 (CCR2-64I) and a 32-bp deletion in the coding region of CCR5 (CCR5Delta32), which leads to the expression of a nonfunctional receptor. The distribution of the CCR2-64I and CCR5Delta32 polymorphisms was determined in 290 AD patients and in 222 controls. A decreased frequency and an absence of homozygous for the polymorphism CCR2-64I were found, thus suggesting a protective effect of the mutated allele on the occurrence of AD. However, these findings must be cautiously interpreted as the overall significance was found without adjustment for multiple comparisons and is coming from the complete absence of the genotype 64I/64I in AD patients. Conversely, no different distribution of the CCR5Delta32 deletion in the two populations was shown. Stratifying by the presence of ApoE varepsilon4 allele, gender or age at onset, no differences in either allele frequencies were observed.

Fenoglio C, Galimberti D, Lovati C, Guidi I, Gatti A, Fogliarino S, Tiriticco M, Mariani C, Forloni G, Pettenati C, Baron P, Conti G, Bresolin N, Scarpini E. · Department of Neurological Sciences, "Dino Ferrari" Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. · Neurobiol Aging. · Pubmed #15312962 No free full text.

Abstract: MCP-1 levels are increased in CSF of patients with Alzheimer's disease (AD) compared with controls, suggesting a role in the development of dementia. Recently, a biallelic A/G polymorphism in the MCP-1 promoter at position -2518 has been found, influencing the level of MCP-1 expression in response to an inflammatory stimulus. The distribution of the A-2518G SNP was determined in 269 AD patients and in 203 healthy age matched controls, showing no differences between the two groups. On the contrary, a significant increase of MCP-1 serum levels in AD patients carrying at least one G mutated allele was observed. Moreover, the highest peaks of MCP-1 serum levels were present in patients carrying two G alleles. Stratifying by ApoE genotype, gender or age at onset, no differences in both allele frequency and MCP-1 serum concentration were observed. The A-2518G polymorphism in MCP-1 gene does not seem to be a risk factor for the development of AD, but its presence correlates with higher levels of serum MCP-1, which can contribute to increase the inflammatory process occurring in AD.

Galimberti D, Venturelli E, Fenoglio C, Lovati C, Guidi I, Scalabrini D, Mariani C, Bresolin N, Scarpini E. · No affiliation provided · Eur J Neurol. · Pubmed #17388976 No free full text.

This publication has no abstract.