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The study analyses the performance of 22 mild Alzheimer's disease (AD) patients on the Release from Proactive Interference (RPI) paradigm with the aim to investigate the relationship of RPI with frontal function. Twenty-one normal elderly subjects, age and education matched, constituted the control group. Patients with AD were found to recall less words on each trial of the RPI than did the controls. The analysis of Proactive Interference (PI) and Release from PI, in AD patients, by using Anova (trial x group), showed a significant effect of trial and group but not a group by trial interaction. These results indicate a similarity between the performance of AD patients and normal controls on the Release from Proactive Interference paradigm. Despite the similar pattern of performance, AD patients were significantly inferior to normal controls with regard to global performance level. The AD patients' scores on "frontal lobe" tests were correlated with an index of RPI (shift condition index). The only significant result was with the number of categories on the Wisconsin Card Sorting Test, suggesting a weak correlation between RPI and "frontal lobe" function.

In order to study the strategies of access to semantic knowledge and the status of semantic representation, we analyzed the performance in a semantic fluency task (Animal naming) of 70 patients with probable Alzheimer's disease (AD), including 40 mild AD patients and 30 moderate-severe AD patients, and 35 matched elderly normal control subjects. The total amount of words produced, their lexical frequency, the number and type of errors, as well as the presence and the type of clusters of related animal names were recorded. AD patients produced less animal exemplars than controls. In addition to a lower total number of clusters, the AD patients showed a strong limitation in clusters' selection, producing a limited number of different clusters. While normal subjects produced several different clusters, only farm animals were clustered by AD patients. When the total amount of words was considered, the mean lexical frequency was higher in the AD group. On the other hand, the words produced within clusters were comparable to terms of lexical frequency and number. These data confirm the impairment of AD patients in category fluency tasks, and suggest a degradation of semantic knowledge as the most likely underlying mechanism.

Several factors have been reported to predict death and institutionalization in demented patients, even if the results of the studies are often conflicting. We conducted a study on a group of 86 consecutive noninstitutionalized probable Alzheimer disease (AD) patients, to evaluate clinical and social factors predicting mortality and institutionalization 1 year after discharge from the Alzheimer Dementia Unit at ''Sacro Cuore Fatebenefratelli’ Hospital, Brescia, Italy. The 1-year mortality rate was 13.9% and the 1-year rate of admission to a nursing home was 34%. Our data indicate that the number of lost functions on the Activity of Daily Living scale is the most important predictor of short-term mortality, independently of the degree of cognitive impairment, the duration of the dementia, the age of the patients and the number of chronic diseases. Our data also demonstrate that, in a short period of observation, behavioral disturbances (and in particular insomnia) and availability of social Services play a major role in the decision to institutionalize AD patients.

Frontotemporal dementia (FTD) is a clinical entity grouping different diagnostic conditions. FTD can occur in a sporadic form; however in 30-50% of cases a familial form of FTD has been observed. Mutations in the TAU gene were associated to familial FTD linked to chromosome 17. Our aim was to investigated the proportion of FTD cases attributable to TAU gene mutations in an Italian clinical series. We analyzed 38 patients with FTD; of these, 13 had a positive family history of FTD. All TAU gene exons and flanking intronic regions were sequenced. In our familial FTD sample the estimation of TAU gene mutations accounted for a relative low prevalence (7.6%); based on our results we could argue the existence of other mutations in regulatory regions in the TAU gene or, on the other hand, other genes might be responsible for the most cases of familial FTD.

We evaluated the relationship between brain rhythmicity and both the cerebrovascular damage (CVD) and amygdalohippocampal complex (AHC) atrophy, as revealed by scalp electroencephalography (EEG) in a cohort of subjects with mild cognitive impairment (MCI). All MCI subjects underwent EEG recording and magnetic resonance imaging. EEGs were recorded at rest. Relative power was separately computed for delta, theta, alpha1, alpha2, and alpha3 frequency bands. In the spectral band power the severity of CVD was associated with increased delta power and decreased alpha2 power. No association of vascular damage was observed with alpha3 power. Moreover, the theta/alpha1 ratio could be a reliable index for the estimation of the individual extent of CV damage. On the other side, the group with moderate hippocampal atrophy showed the highest increase of alpha2 and alpha3 power. Moreover, when the amygdalar and hippocampal volumes are separately considered, within amygdalohippocampal complex (AHC), the increase of theta/gamma ratio is best associated with amygdalar atrophy whereas alpha3/alpha2 ratio is best associated with hippocampal atrophy. CVD and AHC damages are associated with specific EEG markers. So far, these EEG markers could have a prospective value in differential diagnosis between vascular and degenerative MCI.

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). Cognitive deficits are prevalent in patients with schizophrenia (SCZ) and worsen with old age. We recently reported that elderly SCZ patients show reduced levels of amyloid-beta (Aβ)1-42 in cerebrospinal fluid (CSF). To further clarify the role of Aβ in cognitive decline, we analyzed the whole panel of CSF Aβ isoforms in elderly SCZ patients as well as in sporadic AD using SELDI TOF MS. The immunoproteomic study revealed, in all analyzed CSF samples, the presence of 15 different Aβ peptides. In CSF from SCZ, we detected an overall strong reduction of almost all Aβ species while in sporadic AD Aβ1-42 was the only peptide reduced. A significant independent association between Aβ1-40 levels and global cognition was found in SCZ. In addition, in SCZ patients, duration of therapy was positively associated with soluble amyloid precursor protein alpha levels, the total amount of CSF Aβ and the most abundant Aβ1-40 isoform. These data suggests a dysmetabolism of amyloid precursor protein in older SCZ patients. Thus, the quite comparable reduction of CSF Aβ1-42 in AD and in elderly SCZ patients reflects different pathophysiological dynamics in ageing brain.

Transcription factor Sp4 (Specificity protein 4) levels are increased in the brain of patients with Alzheimer's disease (AD), and Sp4 colocalizes with neurofibrillary tangles. Moreover, SP4 is a susceptibility gene for bipolar disorder and schizophrenia, which share many clinical features with frontotemporal lobar degeneration (FTLD). The distribution of three tagging single nucleotide polymorphisms (SNPs)-rs9639379, rs10272006, and rs6461569-has been determined in a population of 352 patients diagnosed clinically with AD, 290 patients with FTLD, and 341 age-matched controls. Expression analysis of SP4 was performed in peripheral blood mononuclear cells (PBMC). No significant differences in either allelic or genotypic frequency of the three SNPs were found (p > 0.05), even stratifying according to gender and to the apolipoprotein E status. Significantly increased SP4 relative expression levels were observed in PBMC from patients with AD as compared with controls (7.132 +/- 1.301 versus 3.396 +/- 0.829, p < 0.050) and a similar trend was shown in patients with FTLD compared with controls (6.525 +/- 1.500 versus 3.396 +/- 0.829, p = 0.073). According to these results, SP4 gene does not act as a susceptibility factor either for AD or FTLD. However, Sp4 mRNA levels are upregulated in patients, possibly resulting in an aberrant expression of downstream target genes involved in the pathogenesis of both diseases

Alzheimer's disease (AD) is a neurodegenerative disorder often treated with donepezil, an acetylcholinesterase inhibitor. Response to donepezil is variable, probably based on patients' genetic background in donepezil metabolizing enzymes, including cytochrome 2D6 (CYP2D6). We evaluated the association between clinical response to donepezil and a common variant (rs1080985) of CYP2D6, previously reported to be associated with poor response to the drug. In a sample of 415 AD cases, we found evidence of association between rs1080985 and response to donepezil after 6 months of therapy (OR [95% CI]: 1.74 [1.01-3.00], p = 0.04). Rs1080985 might be useful as predictor of poor response to short-term donepezil treatment.

In the present study we have examined the distribution of several isoforms of protein kinase C, a lipid-regulated serine/threonine kinase essential for signal transduction and cell regulation, in cultured human skin fibroblasts. By Western blot analysis we have detected the presence of at least three of the known protein kinase C isoforms. The calcium-dependent protein kinase C alpha was primarily associated with the cytosolic fraction. Three non-calcium-dependent isoforms, protein kinases C epsilon, C delta, and C zeta, were also detected. Protein kinases C zeta and C delta were present primarily in the cytosol, while protein kinase C epsilon was associated primarily with the membrane fraction. Binding and activity studies were consistent with the pattern of expression and distribution defined by Western blot analysis. These results provide a useful frame of reference for the study of isoform-specific effects of protein kinase C in the regulation of cell growth and metabolism.

Background Human sirtuins are a current hotspot for research in neurodegenerative disorders, including Alzheimer's disease (AD). This study investigated whether genetic variants in two members of the sirtuin family, SIRT2 and SIRT3 , affected AD susceptibility. Methods A genetic case–control study was performed, comprising 534 probable AD cases and 638 nondemented control subjects from the north of Italy and Canton Ticino, Switzerland (discovery population). The study was focused on SIRT2 rs10410544, SIRT3 rs4980329, and SIRT3 rs536715 single nucleotide polymorphisms (SNPs). These SNPs were genotyped by real-time polymerase chain reaction allelic discrimination assay or restriction fragment length polymorphism. The SNPs rs7412 and rs429358, mapping within the apolipoprotein E ( APOE ) gene, were genotyped by real-time polymerase chain reaction allelic discrimination assay too. In a replication population comprising 756 AD cases and 847 nondemented control subjects, SIRT2 rs10410544, APOE rs7412, and APOE rs429358 were genotyped as mentioned previously. Results In the discovery population, we observed an association between SIRT2 rs10410544 T allele and AD (adjusted odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.02–1.50, P = .02, after correction for sex, age, and APOE ɛ4 genotype). The association between AD and SIRT2 rs10410544 T allele was only present in APOE ɛ4 noncarriers (adjusted OR=1.29, 95% CI: 1.03–1.61, P = .03). The replication study did not confirm this evidence. However, the combined analysis on the two cohorts detected the association (adjusted OR=1.17, 95% CI: 1.02–1.35, P = .02), and only APOE ɛ4 noncarriers were at risk (adjusted OR=1.2, 95% CI: 1.02–1.43, P = .03). Conclusions The SIRT2 rs10410544 T allele deserves further investigation as a novel minor genetic risk factor for AD in the APOE ɛ4-negative Caucasian population.

Background Gray matter (GM) changes of thalamus and basal ganglia have been demonstrated to be involved in Alzheimer's disease (AD). Moreover, the increase of two EEG markers, alpha3/alpha2 and theta/gamma ratio, have been associated with, respectively, AD converter and non-AD converter subjects with mild cognitive impairment (MCI). Objective To study the association of prognostic EEG markers with specific GM changes of thalamus and basal ganglia in subjects with MCI to identify different MCI populations. Methods 74 adult subjects with mild cognitive impairment underwent EEG recording and high resolution 3D magnetic resonance imaging (MRI). The theta/gamma and alpha3/alpha2 ratio was computed for each subject. Three groups were obtained according to increasing tertile values of both alpha3/alpha2 and theta/gamma ratio. Gray matter density differences between groups were investigated using a voxel-based morphometry technique. Results Subjects with higher a3/a2 ratios when compared to subjects with lower and middle a3/a2 ratios showed minor atrophy in the ventral stream of basal ganglia (head of caudate nuclei and accumbens nuclei bilaterally) and of the pulvinar nuclei in the thalamus; subjects with higher t/g ratio showed minor atrophy in putamina nuclei bilaterally than subjects with middle ratio. Conclusion The integrated analysis of EEG and morpho-structural markers could be useful in the comprehension of anatomo-physiological underpinning of the MCI entity.

The initiating event in Alzheimer's disease (AD) is an imbalance in the production and clearance of amyloid beta (Aβ) peptides leading to the formation of neurotoxic brain Aβassemblies. Cerebrospinal Fluid (CSF), which is a continuum of the brain, is an obvious source of markers reflecting central neuropathologic features of brain diseases. In this review, we provide an overview and update on our current understanding of the pathobiology of human CSF Aβpeptides. Specifically, we focused our attention on the heterogeneity of the CSF Aβworld discussing (1) basic research studies and what has been translated to clinical practice, (2) monomers and other soluble circulating Aβassemblies, and (3) communication modes for Aβpeptides and their microenvironment targets. Finally, we suggest that Aβpeptides as well as other key signals in the central nervous system (CNS), mainly involved in learning and hence plasticity, may have a double-edged sword action on neuron survival and function.

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-β42, 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.

The aim of the present study was to identify which factors may predict the best response to a comprehensive stimulation program in patients with dementia and mild cognitive impairment (MCI) as well as in their caregivers.A six-month longitudinal study has been performed on 145 patients (55 with MCI and 90 with dementia), participating to a cognitive motor rehabilitation program, and their 131 caregivers, attending informational/psychoeducational interventions. Mini mental state examination, Alzheimer's Disease Assessment Scale-Cognition, and Clinician's Interview-Based Impression of Change-plus were used as primary outcome measures.Sixty-eight (46.9%) of the 145 subjects were classified as clinical responders. At baseline, responders had a significant less insight impairment, larger functional ability as well as less delusions, euphoria, and aberrant motor behaviors than the non-responder. After 6 months along with an improvement in cognition, responders showed decrease in behavioral disturbances and severity of the disturbances. During the 6 months of analysis, stability has been observed in caregiver's burden distress. After 6 months, the caregivers of MCI responders have their burden reduced.The high level of insight, the preserved functional abilities as well as the lack of severe delusions, euphoria, and aberrant motor behaviors are significant predictors of responsiveness to stimulation program.

This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the e4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (-491 rs449647, -427 rs769446, -219 rs405509, and e rs429358-rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants -219T and e4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in phase); 2) the correlation between the haplotype (-219T/e4) and AD risk persists when the data are stratified by age; 3) this haplotype likely anticipates the age of onset of the disease. These data, while confirming the association between -219T and AD, highlight the importance of the phase of the alleles for the observed effects on AD risk, suggesting that this information has to be taken into account when assessing the AD genetic risk. Moreover, the data help to clarify the apparent discrepancy that emerges from the genetic analysis where an SNP characterizing the haplotype responsible for an increased risk for LOAD is coherently associated with a reduced expression of ApoE levels. Our data are compatible with the hypothesis of a complex role of ApoE in the AD pathogenesis, with positive and negative effects occurring concomitantly according to its expression levels and its protein-protein interactions largely unclarified.

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. © 2011, Mary Ann Liebert, Inc.

In patients affected by Alzheimer's disease (AD), serum copper not bound to ceruloplasmin ('free' copper) appears elevated, slightly but significantly enough to distinguish AD patients from healthy elderly subjects. In this paper we tested the hypothesis that this is also the case for individuals affected by mild cognitive impairment (MCI). A sample of 83 MCI subjects were compared with 100 elderly control subjects in terms of levels of serum copper, free copper, ceruloplasmin, apolipoprotein E4 genotype (APOE4), iron, transferrin, and total antioxidant capacity (TRAP). The groups were also compared in terms of demographic and cardiovascular risk factors. The comparison with an additional group of 105 mild to moderate AD patients was also evaluated. The possible effects of copper dysfunction on cognitive decline were evaluated by multinomial logistic regression analysis. A linear regression model was applied to define the role of metals and antioxidant dysfunction in explaining Mini-Mental Status Examination (MMSE) variations. APOE4 and free copper differentiated the MCI group from the healthy control group. The probability of acquiring MCI increased by about 24% for each free copper unit (μmol/L) increment. APOE4 and free copper differentiated the MCI group also from the AD group. APOE4 and free copper appeared associated to MMSE worsening, as did age and gender. These results suggest that free copper can help in discriminating MCI subjects from healthy controls, but not on an individual basis.

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioural disturbances and cognitive decline. Here we describe an Italian family with FTLD showing remarkable phenotypic heterogeneity. Based on low plasma levels of progranulin, we analyzed the progranulin gene (GRN) in two patients with early onset and found the novel frame-shift mutation T278SfsX7. mRNA analysis confirmed the null effect of the mutation. The patients were homozygous for H1 MAPT haplotype, a disease modifier factor that can account for early age at onset. Being predictive for GRN null mutations, plasma progranulin dosage should be included in diagnostic work-up of dementia.

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.

A recent genome-wide study on late-onset Alzheimer's disease identified a SNP (rs5984894) on Xq21.3 in the PCDH11X gene strongly associated with LOAD individuals of European descent from the United States. We genotyped the same polymorphism in 1222 cases and 938 controls from central-northern Italy and could not confirm the association on the Italian population: multivariate logistic regression adjusted for gender and APOE epsilon 4 allele resulted in a global p value of 0.56.

Acetylcholinesterase inhibitors (AChEIs) have been used to improve cognitive status and disability in patients with mild to moderate Alzheimer's disease (AD). However, while the efficacy of AChEIs (i.e. how they act in randomized controlled trials) in this setting is widely accepted, their effectiveness (i.e. how they behave in the real world) remains controversial. To compare the effects of three AChEIs, donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon), in an Italian national, prospective, observational study representative of the 'real world' clinical practice of AChEI treatment for AD. 938 patients with mild to moderate AD collected within the framework of the Italian National Cronos Project (CP), involving several UVAs (AD Evaluation Units) spread over the entire national territory, who were receiving donepezil, galantamine or rivastigmine were followed for 36 weeks by measuring: (i) function, as determined by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [primary outcome measures]; and (iii) behaviour, as measured on the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale. Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic variants. No statistically significant improvement in the primary outcome measures (MMSE and ADAS-Cog) was observed with drug therapy at 36 weeks, at which point all groups had lost, on average, 1 point on the MMSE and gained 2-3 points on the ADAS-Cog scale compared with baseline. On the secondary outcome measures at week 36, all treatment groups showed a significant worsening on the ADL and IADL scales compared with baseline, while on the NPI scale there were no significant differences from baseline except for the galantamine-treated group which worsened significantly. Moreover, patients receiving galantamine worsened significantly compared with the donepezil-treated group on the IADL scale. ApoE epsilon4 allele did not influence the effect of drug therapy. Over a 36-week follow-up period, no significant difference in the effects of donepezil, galantamine and rivastigmine on a variety of functional and cognitive parameters was observed in a large number of apoE-genotyped patients with mild to moderate AD recruited within the framework of a national project representative of the scenario usually encountered in actual clinical practice in Italy. The limitations (possibility of administration of lower drug doses than are used in clinical trials, relatively short follow-up period and the lack of randomization) and strengths (large number of patients, concomitant observation of the three drugs and the number of parameters assessed, including apoE genotype) of the present study are acknowledged. Our type of naturalistic study should complement clinical trials because 'real world' practice operates in the face of the numerous variables (e.g. health status and co-morbidities) associated with a complex disease such as AD in elderly people.

Mutations in the progranulin gene (GRN) are responsible for familial FTLD with ubiquitin pathology (FTLD-U). However, there are controversial data regarding the contribution of GRN variability to sporadic FTLD. We carried out an association study in 265 patients, who did not carry a GRN causal mutation, and 375 age-matched controls. Four tagging Single Nucleotide Polymorphisms (SNPs) were chosen generate 80% power to detect an allelic association with P ≤ 0.01. In addition, a known functional SNP (rs5848) was included. An increased frequency of the rs4792938 CC genotype in cases compared with controls was observed (17.4 versus 10.4%, P=0.01, OR: 1.81, 95%CI: 1.15-2.85). Stratifying for gender, no differences were observed for all polymorphisms. Haplotype analysis failed to detect haplotypes associated with the disease. Our findings indicate that the GRN rs4792938 CC genotype represents a susceptibility factor for the development of FTLD in individuals who do not carry GRN causal mutations. This SNP is likely located in a regulatory region, thus an effect on GRN mRNA levels may be of mechanistic importance. © 2010 - IOS Press and the authors. All rights reserved.

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.

BackgroundAlzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD.Methodology/principal findingsWe applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR=1.85, 95% CI:1.04-3.23) in particular for females (OR=2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p=0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p=0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls.ConclusionsOur results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.

Linkage analysis identified a region on chromosome 9p associated with Frontotemporal Lobar Degeneration (FTLD). A detailed analysis of candidate genes lying in this region demonstrated an association with Ubiquitin Associated Protein (UBAP)1. The distribution of five Single Nucleotide Polymorphisms (SNPs) located in the chromosome 9 haplotype identified via linkage analysis, including UBAP1 rs7018487, UBAP2 rs1785506 and rs307658, and KIF24 rs17350674 and rs10814083, has been determined in a population of 284 patients diagnosed with FTLD, including 245 with behavioural variant Frontotemporal Dementia (bvFTD), 23 with Progressive Aphasia and 16 with Semantic Dementia, compared with 318 age-matched controls. A statistically significant increased frequency of the KIF24 rs17350674 AA genotype was observed in patients compared with controls (7.4 versus 2.5%; P= 0.0068, OR: 3.63, CI: 1.58-8.35). Considering each syndrome separately, similar results where obtained in bvFTD versus controls (7.7 versus 2.5%, P= 0.005, OR: 3.26, CI: 1.40-7.57). Stratifying for gender, a statistically significant increased genotypic frequency was observed in female patients as compared with female controls (8.9 versus 2.5%, P= 0.008, OR: 3.85, CI: 1.36-10.93). In silico analysis predicted that the substitution from W to L caused by the rs17350674 affects protein function (P< 0.05). The KIF24 rs17350674 polymorphism likely acts as a risk factor for sporadic FTLD, but a replication study would be needed to confirm these preliminary findings. © 2010 Elsevier Ireland Ltd.

A novel missense mutation (T719P) in the amyloid-beta protein precursor (AbetaPP) gene was discovered in a 46-year old patient affected by early onset familial Alzheimer's disease. Using surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS), we determined mass profiles of amyloid-beta peptides (Abeta) in cerebrospinal fluid (CSF) of the AbetaPP mutated patient, healthy control subjects (n = 10), and of two subjects carrying mutations in presenilins genes (PS) (i.e., PS1 P117L and PS2 T122R): seven different C-terminally and three N-terminally truncated Abeta peptides were found in CSF. The investigated AbetaPP as well as PS mutations were associated with an overall reduction of Abeta species, except for Abeta(10-40). Interestingly, the AbetaPP T719P mutation unbalanced the relative proportion of Abeta peptides with a reduction of Abeta(1-40) and Abeta(1-42) paralleled by an increase of Abeta(1-38) and Abeta(10-40). Despite the specific neuropeptidomic phenotype associated with the AbetaPP T719P mutation, the enrichment in Abeta(10-40) paralleled by depletion of Abeta(1-42) seems to be a common theme in familial AD. The AbetaPP T719P mutation is of particular interest because it is the only mutation located in close proximity to the AbetaPP epsilon-cleavage site.

We evaluated the association between amygdalo-hippocampal complex (AHC) atrophy and two electroencephalography (EEG) markers of cognitive decline: increase of theta/gamma and increase of alpha3/alpha2 relative power ratio. Seventy-nine subjects with mild cognitive impairment (MCI) underwent EEG recording and magnetic resonance imaging scan. Based on the tertiles values of decreasing AHC volume, three groups of AHC growing atrophy were obtained. The groups were characterized by the performance to cognitive tests and theta/gamma and alpha3/alpha2 relative power ratio. AHC atrophy is associated with memory deficits as well as with increase of theta/gamma and alpha3/alpha2 ratio. Moreover, when the amygdalar and hippocampal volume are separately considered within AHC, the increase of theta/gamma ratio is best associated with amygdalar atrophy whereas alpha3/alpha2 ratio is best associated with hippocampal atrophy. AHC atrophy is associated with memory deficits and EEG markers of cognitive decline. So far, these EEG markers could have a prospective value in differential diagnosis between patients with MCI who develop dementia and those who do not as well as between MCI patients who will develop Alzheimer's disease and those who develop non-Alzheimer's disease dementias. The alterations of the functional connections, inducing global network pathological changes, in the whole AHC could better explain MCI state.

Alzheimer's Disease Neuroimaging Initiatives ("ADNI") aim to validate neuroimaging and biochemical markers of Alzheimer's disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported.Six academic EADC centres recruited 49 subjects (healthy controls, subjects with mild cognitive impairment (MCI) and AD). We measured CSF beta-amyloid 42 (CSF Abeta42), total tau-protein (t-tau), phosphorylated tau-proteins (P-tau181, P-tau231), plasma beta-amyloid 40 and 42 (Abeta40/Abeta42). Immediate fresh shipment was compared to freezing and later shipment on dry ice.CSF T-tau (fresh samples) was increased in AD versus controls (p=0.049), CSF Abeta42 (frozen samples) was decreased in MCI and AD (p=0.02), as well as plasma Abeta40 (fresh and frozen samples) in AD (p=0.049 and p=0.016). Pooled values of neurochemical parameters and ratios thereof were different between centres (p0.005). Analysis of frozen samples yielded higher diagnostic accuracy than immediate fresh shipment with 100% (fresh: 100%) correctly classified in control subjects, 100% (78%) in MCI, 91% (91%) in AD.The use of frozen rather than fresh samples renders higher diagnostic accuracy within a multicentre context. We confirmed the feasibility of a multicentre AD biomarker programme for future clinical trials.

CCL2/Monocyte Chemoattractant Protein (MCP)-1 and other chemokines sharing a similar sequence, including CCL8/MCP-2, are involved in neurodegeneration. A few Single Nucleotide Polymorphisms (SNPs) have been reported in CCL8/MCP-2, all of which are located in the same linkage block. One of them (rs1163763) leads to an aminoacidic substitution, implying a potential impact on the function of the protein. rs1133763 was tested for association in 219 patients with Alzheimer's disease (AD) and 209 with Frontotemporal Lobar Degeneration (FTLD) as compared with 231 age-matched controls. The distribution of CCL8/MCP-2 rs1133763 was not significantly different among patients with AD or FTLD and controls, even stratifying according to gender. CCL8/MCP rs1133763 SNP, or other variants in linkage disequilibrium with this variant, likely do not influence the susceptibility to AD or FTLD in Caucasians. © 2009 Springer-Verlag.

The distribution of the MCP-1 A-2518G single nucleotide polymorphisms (SNP) was analyzed in a population of 212 patients with frontotemporal lobar degeneration (FTLD) compared with 203 age-matched controls. A significantly decreased allelic frequency of the G allele in patients compared with controls was observed (21.1 versus 29.3%, P = 0.011, OR: 0.59, CI: 0.40-0.87). Stratifying according to gender, the association was maintained in male patients versus male controls (17.8 versus 29.4%, P = 0.016, OR = 0.46, 95% CI: 0.25-0.84), but not in female patients compared with female controls (23.5 versus 29.2%, P > 0.05). The frequency of apolipoprotein E ε4 carriers was increased in patients (26.4 versus 13.8%, P = 0.0015, OR: 2.24, 95% CI: 1.37-3.67). Apolipoprotein E status did not influence the distribution of the A-2518G SNP. Monocyte chemotactic protein (MCP)-1 levels were determined in cerebrospinal fluid (CSF) collected from 23 patients and 17 controls. MCP-1 CSF levels were increased in patients compared with controls (449.01 ± 27.57 versus 364.19 ± 23.75 pg/ml, P = 0.011). Stratifying patients according to the presence of the polymorphic allele, significantly increased CSF MCP-1 levels were observed in carriers of the G allele compared with non-carriers (502.21 ± 44.57 versus 395.87 ± 21.92 pg/ml, P = 0.045). The MCP-1 A-2518G SNP acts as protective factor for sporadic FTLD, possibly by influencing MCP-1 production. © 2009 - IOS Press.

Due to the rapid emergence of new tools for discovery, empiricism dominated health science in the twentieth century [1]. Monogenic genetic disorders occur as a result of a mutation in a single gene. However, many late onset monogenic neurodegenerative diseases have been found to exhibit more complex inheritance patterns and genotype–phenotype correlations remain inadequately correlated. For example, mutations in progranulin gene are associated with a number of neurodegenerative diseases ranging from frontotemporal dementia (FTD), corticobasal degeneration, Alzheimer disease (AD) to Parkinson disease and Amyotrophic Lateral Sclerosis. Particularly, broad phenotypic expression variability between or within pedigrees bearing the same mutation [2] characterizes many monogenic conditions and appears to be a common scenario in clinical genetics. A middle ground exists whereby inheritance may be atypical due to factors that may modify gene expression or phenotypic severity: thus the brain partially escape genetic determinism. On the other hand, environmental/unidentified factors show an unexpected deterministic tendency to produce sporadic nongenetically determined forms of the disease in the vast majority of cases. The recognition that non-monogenic as well monogenic forms of dementia (i.e. sporadic/familial AD or FTD etc) result substantially in the same disease, suggests that fundamental, simple mechanisms may underlie the apparent complexity of observed human neurodegenerative diseases. Abnormal protein accumulation characterizes a large number of late onset neurodegenerative disorders [3], thus leading to a classification based on the composition of the abnormal protein inclusions (tauopathies, synucleinopathies, TDP-43 proteinopathies) [4]. Although empiricists have atomized medicine into an expanding compendium of named human diseases, the brain capability of neuropathological manifestations might be exiguous, hinging on the anatomical brain areas and neuron phenotypes affected instead of etiopathogenetic mechanism. We believe that the fight against neurodegeneration will be won when a theoretical approach to the comprehension of the mechanisms common to these particular disease sets will be applied. We have to forget the ‘‘specificity” of each disease/protein and, as Aristotle did, to focus on logical sequence of observed phenomena.

BACKGROUND AND PURPOSE The Homeobox A1 (HOXA1) gene plays a critical role during development of the hindbrain in mice. Little is currently known about the relation between this gene and human brain development. The HOXA1 A218G polymorphism has been found to be associated with autism and larger head circumference in autistic patients. Similar effects were revealed also in healthy children but not in adult controls. The aim of this study was to investigate the role of the A218G polymorphism on the hindbrain structure of healthy adults. METHODS Healthy persons from two independent groups underwent 3-dimensional high resolution magnetic resonance (MR) exam. Group A was made of 80 persons (27 G allele carriers and 53 non-carriers) and Group B of 72 (26 carriers and 46 non-carriers). Statistical parametric mapping 2 (SPM2) were used to perform voxel-based analysis of the gray matter (GM) of the hindbrain in carriers and non. Significance threshold was set at .05 with small volume correction using a cerebellar mask. RESULTS In Group A, G carriers exhibited decreased GM volume in the superior posterior and anterior lobe of the cerebellum bilaterally. In Group B, decreased GM volume were found across the entire left cerebellar cortex. CONCLUSIONS These data suggest that the HOXA1 A218G polymorphism may affect cerebellar development in humans.

The microtubule-associated protein Tau (MAPT) gene codes for the protein Tau that is involved in the pathogenesis of neurodegenerative diseases. Recent studies have detected an over-representation of the H1 haplotype of the MAPT gene in neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and Parkinson's disease (PD), whereas the H2 haplotype has been found to be related to familial FTD. We aimed to investigate the association between MAPT haplotype status and brain morphology in healthy adults. A total of 150 healthy subjects underwent 3D high-resolution magnetic resonance (MR). MR images were processed following an optimized protocol to perform the Voxel-based morphometry (VBM) comparisons of the gray matter (GM) in H1 carriers (n=141) in contrast to H2H2 homozygous (n=9), and H1H1 homozygous (n=85) in contrast to H2 carriers (n=65). The threshold for statistical significance was 0.005 uncorrected. Opposite comparisons were also carried out. The groups had similar demographic and cognitive features. Compared with H2H2, the H1 carriers showed up to 19% smaller GM volume in the head of the right caudate nucleus, in the right middle frontal gyrus, in the left insula and orbito-frontal cortex, and in the inferior temporal and inferior cerebellar lobes, bilaterally. Compared with all H2 carriers, H1H1 displayed lower GM in the same regions, but the effect was smaller (5%), possibly due to a dilution effect by H1 in the H2 carriers group. The data suggest that H1 haplotype is associated with a particular cerebral morphology that may increase the susceptibility of the healthy carriers to develop neurodegenerative diseases such as sporadic tauopathies.

Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration (FTLD). Herein we estimated the contribution of the PGRN Leu271LeufsX10 mutation to FTLD and related disorders in the Brescia cohort. The PGRN Leu271LeufsX10 mutation was found in 31% of corticobasal syndrome (CBS), 29% of frontotemporal dementia with motorneuron disease (FTD-MND), 15% of behavioral variant frontotemporal dementia (FTD), 9.5% of primary progressive aphasia (PPA), 2% dementia with Lewy bodies and 0% of progressive supranuclear palsy and multiple system atrophy cases. The prevalence strongly increased in familial forms (75% CBS, 50% FTD-MND, 27% FTD, 18% PPA): in our cohort this mutation is a major disease determinant for FTLD-related disorders with a prominent motor component. MAPT haplotype was demonstrated to be a disease modifier in PGRN Leu271LeufsX10 carriers: in H1H2 subjects the disease onset was earlier than in H2H2 individuals. Sequencing of the whole PGRN gene disclosed a previously described mutation (c.2T>C, Met1X) and three novel ones (c.709-3; c.1011delG, His340ThrfsX21; c.1021C>T, Gln341X) in single families. In the Brescia cohort, while MAPT mutations have low prevalence, mutations in PGRN were shown in 28% of familial FTLD and 75% of familial CBS cases. The PGRN Leu271LeufsX10 mutation becomes one of the most common mutations worldwide, since it was identified in 38 patients belonging to 27 unrelated families.

The working hypothesis of paper is that the functional coupling of brain areas is combined with different neuroradiological substrates and has different clinical manifestations. 31 normal old subjects and 85 subjects with mild cognitive impairment (MCI) underwent EEG recordings and magnetic resonance imaging (MRI). Intrahemispheric and interhemispheric linear EEG coherences were computed. At first, all normal old and MCI subjects were compared. Subsequently, three subgroups of MCI were obtained based on neuroradiological substrate (subcortical cerebrovascular damage, MCI-CVD; cholinergic pathways vascular damage MCI-CHOL; and hippocampal atrophy, MCI-HIPP) and compared with a normal old sample matched for age, education and Mini-Mental State Examination score. The group of MCI subjects compared to normal old subjects shows: 1) decrease of intrahemispheric coherence in fronto-parietal regions (both right and left hemisphere); 2) increase of interhemispheric coherence on frontal regions in delta frequency; and 3) increase of interhemispheric coherence on temporal regions (from delta to alpha3 frequency bands). In the MCI subgroups, hippocampal atrophy is linked to an increase of interhemispheric coherence seen on frontal and temporal regions whereas subcortical CVD is linked to the largest decrease of coherence in fronto-parietal regions. MCI-CVD patients performed worst on Trail Making Test battery whereas MCI-HIPP patients were impaired on Rey word list delayed recall and Rey figure recall.

Background: We have previously shown that fibroblasts from FAD patients carrying mutations in either PS1 (M146L, P117L) or PS2 (M239I, T122R) showed a reduced instead of an exaggerated calcium release from intracellular stores (1-3). These and other PS1/2 mutants (PS1-A246E, PS1-L286V, PS2-N141I), as well as the wild type (wt) forms of these proteins share the same feature when transiently over-expressed in different cell lines and rat primary neurons. Whereas PS1 mutants cause modest reductions under transient expression, PS2 mutants dramatically reduce the store calcium content. Accordingly, the latter also cause lower steady-state calcium concentrations at the level of the endoplasmic reticulum (ER) and Golgi apparatus (3). Methods: By employing both fura-2 and organelletargeted aequorins to monitor calcium concentrations in the cytosolic and the lumen, we here investigate in HeLa, SH-SY5Y and MEFseither wt or devoid of endogenous PSs (DKO MEFs) the mechanisms by which PS2 variants alter store calcium handling. Results: We provide evidence that: i) expression of wt or mutant PS2 reduces the store calcium content both by increasing the ER calcium leakage and by reducing the ER calcium uptake by SERCA pumps; ii) the full-length (FL) but not the mature form of the protein is directly involved in store calcium handling; iii) the effect is completely independent of g-secretase activity since it is not rescued by pre-incubation with enzyme inhibitors or by expression of a loss-of-function mutant (PS2-D366A); iv) the ryanodine receptor and the ribosome translocon complex are not directly involved. Whether FL PS2 variants represent by themselves a leakage pathway (4) or whether their effect is mediated by IP3 receptors is now under investigation. Conclusions: We suggest that, at variance with the majority of FL PS1 mutants that leave unchanged or even overload intracellular calcium stores, making the cells more susceptible to toxic stimuli, FL PS2 mutants, by lowering ER/Golgi calcium levels result in a less aggressive FAD phenotypes.

Background. White matter lesions (WMLs) may contribute to cognitive deficits in patients with mild cognitive impairment (MCI), but their pathogenesis is complex. Fluctuations of blood pressure (BP) over 24 hours and genetic predisposition to develop vascular damage have been implicated. Methods. In 63 MCI patients 65 years old or older, BP was measured both clinically and with ambulatory BP monitoring. Patients were classified in two groups: no/very mild (n = 34) and mild to severe (n = 29) WMLs, based on a visual scale on magnetic resonance (mean age 71.8 +/- 4.7 vs 74.6 +/- 5.1, and female gender 53% vs 66%, respectively). The volume of WMLs was measured by a semi-automatic method, separately for periventricular caps and rim, periventricular confluent, subcortical punctate, and subcortical confluent. Polymorphisms of cystatin C (CST3) and cholesterol 24-hydroxylase (CYP46) genes, putative risk factors for cerebrovascular disease, were determined. Results. The prevalence of cerebrovascular risk factors was similar in the two MCI groups of different WML severity, as well as clinic and ambulatory BP. In patients with mild to severe, but not in those with no/very mild WMLs, the volume of periventricular confluent WMLs increased with increasing daytime systolic BP (regression coefficient.47, 95% confidence interval [CI],.13 to.71 vs.02, 95% CI, -.32 to.36, p =.003 for the difference between slopes). The volume of other WML subtypes was not associated with ambulatory BP. Participants carrying both CST3*B and CYP46*T alleles were overrepresented in the MCI group with mild to severe WMLs (43% vs 17%, p.03). Conclusions. BP and gene putative risk factors for cerebrovascular disease are differentially associated with WMLs in two MCI groups of different WML severity. WMLs might develop for the convergence of innate with acquired factors.

The frequent polymorphism XbaI (A351G) in the estrogen receptor alpha (ERalpha) gene has been associated with some postmenopausal pathologies' risk such as Alzheimer's disease (AD) or cognitive decline. In the present study, we explored whether the XbaI polymorphism leads to different gray matter volumes using voxel-based morphometry (VBM) on 20 magnetic resonance images of healthy postmenopausal women. Subjects carrying the less common XbaI/X allele were contrasted to non-carriers in groups well balanced by relevant confounding variables. The XbaI/X allele carriers displayed clusters ranging from 9 to 28% of tissue reductions in the cerebellar (cluster size, z, stereotactic coordinates: 16 mm(3); 3.17; 14, -94, -38) and cerebral cortex, in particular in the occipital lobe (272 mm(3); 3.76; -38,-68,-16), in the middle frontal gyrus (192 mm(3); 3.71; 38, 12, 38) and in the middle temporal gyrus, while the opposite comparison was negative. The XbaI/X allele in ERalpha gene is associated to smaller gray matter volumes of the cerebral and cerebellar cortex. This allele might increase the susceptibility for senile neurodegenerative conditions, being associated to smaller cerebral reserve.