Francesca Clerici

Multicenter Standardized 18F-FDG PET Diagnosis of Mild Cognitive Impairment, Alzheimer's Disease, and Other Dementias

This multicenter study examined 18F-FDG PET measures in the differential diagnosis of Alzheimers disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI). Methods: We examined the 18F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals (“normals” or NLs), 114 MCI, 199 AD, 98 FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxel-based comparison with generation of disease-specific patterns of cortical and hippocampal 18F-FDG uptake that were then applied to characterize MCI. Results: Standardized disease-specific PET patterns were developed that correctly classified 95% AD, 92% DLB, 94% FTD, and 94% NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. 18F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns. Conclusion: Standardized automated analysis of 18F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia.

Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease.

Upregulation of a number of chemokines, including monocyte chemotactic protein-1 (MCP-1), is associated with Alzheimers 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.

Autosomal Dominant Frontotemporal Lobar Degeneration Due to the C9ORF72 Hexanucleotide Repeat Expansion: Late-Onset Psychotic Clinical Presentation

BACKGROUND A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration (FTLD). Atypical presentations have been described, particularly psychosis. METHODS We determined the frequency of the hexanucleotide repeat expansions in a population of 651 FTLD patients and compared the clinical characteristics of carriers and noncarriers. In addition, we genotyped 21 patients with corticobasal syndrome, 31 patients with progressive supranuclear palsy, and 222 control subjects. RESULTS The pathogenic repeat expansion was detected in 39 (6%) patients with FTLD (17 male and 22 female subjects); however, it was not detected in any corticobasal syndrome and progressive supranuclear palsy patients or controls. Twenty-four of 39 carriers had positive family history for dementia and/or amyotrophic lateral sclerosis (61.5%), whereas only 145 of 612 noncarriers had positive family history (23.7%; p<.000001). Clinical phenotypes of carriers included 29 patients with the behavioral variant frontotemporal dementia (bvFTD; 5.2% of all bvFTD cases), 8 with bvFTD/motor neuron disease (32% bvFTD/motor neuron disease cases), 2 with semantic dementia (5.9% of patients with semantic dementia), and none with progressive nonfluent aphasia. The presentation with late-onset psychosis (median age = 63 years) was more frequent in carriers than noncarriers (10/33 vs. 3/37, p = .029), as well as the presence of cognitive impairment at onset (15/33 vs. 5/37; p = .0039). CONCLUSIONS The repeat expansion in C9ORF72 is a common cause of FTLD and often presents with late-onset psychosis or memory impairment.

Virtual screening approach for the identification of new Rac1 inhibitors.

Rac1 protein is implicated in several events of atherosclerotic plaque development and represents a new potential pharmacological target for cardiovascular diseases. In this paper we describe a pharmacophore virtual screening followed by molecular docking calculations leading to the identification of five new Rac1 inhibitors. These compounds were shown to be more effective than the reference compound NSC23766 in reducing the intracellular levels of Rac1-GTP, thus supporting this approach for the development of new Rac1 inhibitors.

Role of hnRNP-A1 and miR-590-3p in neuronal death: genetics and expression analysis in patients with Alzheimer disease and frontotemporal lobar degeneration

An association study of heterogeneous nuclear ribonucleoprotein (hnRNP)-A1 was carried out in a population of 274 patients with frontotemporal lobar degeneration (FTLD) and 287 with Alzheimer disease (AD) as compared with 344 age- and gender-matched controls. In addition, we evaluated expression levels of hnRNP-A1 and its regulatory microRNA (miR)-590-3p in blood cells from patients and controls. A statistically significant increased frequency of the hnRNP-A1 rs7967622 C/C genotype was observed in FTLD, but not in AD, in patients as compared to controls (23.0 versus 15.4%; p = 0.022, odds ratio [OR] 1.64, confidence interval [CI] 1.09-2.46). Stratifying according to gender, a statistically significant increased frequency of the hnRNP-A1 rs7967622 C/C genotype was observed in male patients as compared to male controls (23.1 versus 11.3%; p = 0.015, OR 2.36, CI 1.22-4.58 but not in females. Considering the rs4016671 single-nucleotide polymorphism (SNP), all patients and controls were wild type. Significantly increased hnRNP-A1 relative expression levels in peripheral blood mononuclear cells (PBMCs) was observed in patients with AD, but not with FTLD, as compared to controls (2.724 ± 0.570 versus 1.076 ± 0.187, p = 0.021). Decreased relative expression levels of hsa-miR-590-3p was observed in patients with AD versus controls (0.685 ± 0.080 versus 0.931 ± 0.111, p = 0.079), and correlated negatively with hnRNP-A1 mRNA levels (r = -0.615, p = 0.0237). According to these findings, hnRNP-A1 and its transcription regulatory factor miR-590-3p are disregulated in patients with AD, and the hnRNP-A1 rs7967622 C/C genotype is likely a risk factor for FTLD in male populations.

Rs5848 Variant Influences GRN mRNA Levels in Brain and Peripheral Mononuclear Cells in Patients with Alzheimer's Disease

Mutations in the progranulin gene (GRN), causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U), could also be associated with Alzheimers disease (AD). The influence of GRN genetic variability on susceptibility to AD and on expression levels in a series of neuropathologically-confirmed AD patients as well as in peripheral mononuclear cells (PBMC) and in cells isolated from cerebrospinal fluid (CSF) was investigated. An association study of rs9897526 and rs5848 was carried out in an Italian population and in a replication population of European American patients and controls. None of the variants tested act as unequivocal susceptibility factor in both populations although rs9897526 anticipated the onset of the disease in the Italian population. GRN expression in the parietal lobe of AD cases showed a 0.76-fold decrease compared with controls (1.31 +/- 0.07 versus 1.73 +/- 0.12, P = 0.0025). Patients carrying the rs5848 TT genotype had the lowest GRN expression levels (0.96 +/- 0.12, P = 0.014). Despite no significant differences were found in the relative PBMC and CSF GRN expression in patients compared to controls, stratifying patients according to the presence of rs5848 T allele, a 0.57-fold decrease in GRN mRNA levels over C carriers was found in PBMC (1.22 +/- 0.23 versus 0.70 +/- 0.12, P = 0.04). Similarly to data obtained in brain samples, patients carrying the TT genotype showed the lowest GRN mRNA levels (TT = 0.46 +/- 0.14, CC = 1.22 +/- 0.23; P = 0.013). These data argue against a direct role of GRN as a susceptibility factor for sporadic AD but support a role of GRN as a disease-modifying gene, possibly contributing to the failure of neuronal survival.

A new synthetic procedure to spiro[cyclohexane-1,3'-indoline]-2', 4-diones

Abstract A new synthetic pathway to spiro[cyclohexane-1,3′-indoline]-2′,4-diones was found starting from 3-chloromethylene-2-indolones 1 and Danishefskys diene 2 . Their synthesis consists of several steps involving the formation of the cycloadducts, the 6-chloro-4-trimethylsilyloxy-2-methoxyspiro[cyclohex-3-en-1,3′-indolin]-2′-one derivatives, transformed into spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones via 6-chloro-spiro[cyclohex-2-en-1,3′-indoline]-2′,4-dione intermediates. The reduction of spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones gave spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7 . Using a ‘one pot reaction’, starting from 1 and 2 , compounds 7 were obtained in satisfactory overall yield.

Expression of the Transcription Factor Sp1 and its Regulatory hsa-miR-29b in Peripheral Blood Mononuclear Cells from Patients with Alzheimer's Disease.

Altered gene expression occurs in central nervous system disorders, including Alzheimers disease (AD). Transcription factor Sp1 (specificity protein 1) can regulate the expression of several AD-related proteins, including amyloid-β protein precursor and tau. Sp1 is regulated by oxidative stress, and Sp1 mRNA was found to be upregulated in AD cortex and hippocampus. The distribution of three single nucleotide polymorphisms (SNPs), including rs7300593, rs17695156, and rs12821290, covering 100% Sp1 genetic variability, has been determined in a population of 393 AD patients as compared with 412 controls. In addition, expression analysis of Sp1 and its regulatory microRNAs (hsa-miR-29b and hsa-miR-375) has been performed in peripheral blood mononuclear cells (PBMCs), together with Sp1 protein analysis. No differences in all three SNP distributions were observed in AD patients as compared with controls. Stratifying according to gender, a significantly decreased frequency of Sp1 rs17695156 T allele was observed in male patients versus male controls. Significantly increased Sp1 relative expression levels were observed in PBMCs from AD patients as compared with controls. Western blot analysis paralleled mRNA increase in AD patients versus controls and correlated positively with Sp1 mRNA levels. Significantly decreased relative expression levels of hsa-miR-29b, but not of hsa-miR-375, were observed in AD patients versus controls and correlated negatively with Sp1 mRNA levels. According to these results, Sp1 and its regulatory hsa-miR-29b are deregulated in AD patients, possibly leading to aberrant production of downstream target genes involved in the pathogenesis. Moreover, Sp1 rs176951056 T allele is likely a protective factor in the male population.

Novel exon 1 progranulin gene variant in Alzheimer's disease

Background and purpose:  Progranulin (PGRN) expression is increased in activated microglia in Alzheimers disease (AD) brain, suggesting a potential role in this pathology.

Palladium-Catalyzed Domino Carbopalladation/5-exo-Allylic Amination of α-Amino Allenamides: An Efficient Entry to Enantiopure Imidazolidinones

Allenamides of alpha-amino acids were converted into enantiopure 2-vinylimidazolidin-4-ones by a carbopalladation/exo-cyclization process. The products were obtained in 2.5:1-5.5:1 dr, with 94-99% ee. The palladium-catalyzed carbonylative cyclization of the same substrates afforded enone structures. Starting from properly substituted allenamides, an intramolecular carbopalladation followed by intramolecular amination gave rise to tricyclic fused-ring imidazolidinones.