Showing papers by "Giuliano Binetti published in 2013"

C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Abstract: Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72 . For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin ( GRN : p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau ( MAPT : p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia

Abstract: Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD-TDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD-TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over-expression. However, over-expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk. We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD-TDP in these patients.

C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: a genotype-phenotype correlation study.

Abstract: Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201) Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier In our cohort, the C9ORF72 pathological expansion: (i) showed a prevalence of 75%; (ii) showed a full penetrance by the age of 80; (iii) was rarely found in sporadic patients; (iv) was solely associated with FTLD; (v) was mainly associated with bvFTD clinical subtype; and (vi) was associated with earlier age of onset in the youngest generation compared with the previous generation within a pedigree Interestingly, intermediate C9ORF72 expansion had a risk effect in familial/sporadic FTLD Eventually, the C9ORF72 repeat units number influenced the disease phenotype in terms of age of onset and associated clinical subtype Genome-wide studies in well characterized clinical cohorts will be essential in order to decipher pathways of disease expression in C9ORF72-associated neurodegeneration

EEG upper/low alpha frequency power ratio relates to temporo-parietal brain atrophy and memory performances in mild cognitive impairment

Abstract: Objective: temporo-parietal cortex thinning is associated to mild cognitive impairment (MCI) due to Alzheimer disease (AD). The increase of EEG upper/low alpha power ratio has been associated with AD-converter MCI subjects. We investigated the association of alpha3/alpha2 ratio with patterns of cortical thickness in MCI. Methods: 74 adult subjects with MCI underwent clinical and neuropsychological evaluation, electroencephalogram (EEG) recording and high resolution 3D magnetic resonance imaging (MRI). Alpha3/alpha2 power ratio as well as cortical thickness was computed for each subject. Three MCI groups were detected according to increasing tertile values of upper/low alpha power ratio . Difference of cortical thikness among the groups was estimated. Pearson’s r was used to assess the topography of the correlation between cortical thinning and memory impairment. Results: High upper/low alpha power ratio group had total cortical grey matter (CGM) volume reduction of 471 mm2 than low upper/low alpha power ratio group (p

The SIRT2 polymorphism rs10410544 and risk of Alzheimer's disease in two Caucasian case-control cohorts.

Abstract: 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.

Increase of theta frequency is associated with reduction in regional cerebral blood flow only in subjects with mild cognitive impairment with higher upper alpha/low alpha EEG frequency power ratio.

Abstract: Background: several biomarkers have been proposed for detecting Alzheimer's disease (AD) in its earliest stages, that is, in the predementia stage. In an attempt to find noninvasive biomarkers, researchers have investigated the feasibility of neuroimaging tools, such as MRI, SPECT as well as neurophysiological measurements using EEG. Moreover, the increase of EEG alpha3/alpha2 frequency power ratio has been associated with AD-converters subjects with mild cognitive impairment (MCI). Objective: to study the association of alpha3/alpha2 frequency power ratio with regional cerebral blood flow (rCBF) changes in subjects with MCI . Methods: 27 adult subjects with MCI underwent EEG recording and perfusion single-photon emission computed tomography (SPECT) evaluation. The alpha3/alpha2 frequency power ratio was computed for each subject. Two groups were obtained according to the median values of alpha3/alpha2, at a cut-off of 1.17. Correlation between brain perfusion and EEG markers were detected. Results: subjects with higher alpha3/alpha2 frequency power ratio showed a constant trend to a lower perfusion than low alpha3/alpha2 group. The two groups were significantly different as about the hippocampal volume and correlation with the theta frequency activity. Conclusion: there is a complex interplay between cerebral blood flow, theta frequency activity and hippocampal volume in MCI patients with prodromal Alzheimer's disease, characterized by higher EEG alpha3 /alpha2 frequency power ratio.

Predictors of comprehensive stimulation program efficacy in patients with cognitive impairment. Clinical practice recommendations.

Abstract: Background 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. Methods 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. Results 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. Conclusions 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. Copyright © 2012 John Wiley & Sons, Ltd.

Relationship between EEG Alpha3/Alpha2 Ratio and the Nucleus Accumbens in Subjects with Mild Cognitive Impairment

Abstract: Background: The nucleus accumbens (NAc) has been associated with impulsive behavior in subjects with early cognitive impairment; grey matter (GM) changes of basal ganglia have been demonstrated to be involved in Alzheimer’s disease (AD). Moreover, the increase of EEG alpha3/alpha2 ratio has been associated with ADconverters subjects with mild cognitive impairment (MCI). Objective: To study the association of EEG marker with specific GM changes of NAc in subjects with MCI Methods: 74 adult subjects with mild cognitive impairment underwent EEG recording and high resolution 3D magnetic resonance imaging (MRI). The alpha3/alpha2 ratio was computed for each subject. Three groups were obtained according to increasing tertiles values of alpha3/alpha2. Grey matter density differences between groups were investigated using a Voxel Based Morphometry technique. Results: Subjects with lower a3/a2 and middle a3/a2 ratio ratio showed greater gray matter reduction in the NAc bilaterally when compared to subjects with higher a3/a2 ratio. Conclusion: The a3/a2 ratio was associated with increase of grey matter density inside the NAc in MCI subjects at major risk to develop AD.

Temporo-Parietal Brain Network Impairment Is Related To EEG ALPHA3/ ALPHA2 Frequency Power Ratio in Prodormal Alzheimer's Disease

Abstract: Background: Reliable biomarkers are the new frontier for an early diagnosis of Alzheimer's disease and to monitor therapeutic options Objective: Volume reduction in temporo-parietal network is associated to mild cognitive impairment (MCI) due to Alzheimer disease (AD). The increase of EEG alpha3/alpha2 ratio has been associated with AD-converter MCI subjects. We investigated the association of alpha3/alpha2 ratio with patterns of cortical thickness in MCI. Methods: 74 adult subjects with MCI underwent clinical and neuropsychological evaluation, electroencephalogram (EEG) recording and high resolution 3D magnetic resonance imaging (MRI). Alpha3/alpha2 power ratio as well as cortical thickness was computed for each subject. Three MCI groups were detected according to increasing tertile values of alpha3/alpha2 and difference of cortical thikness among the groups estimated. Pearson’s r was used to assess the topography of the correlation between cortical thinning and memory impairment. Results: High a3/2 group had total cortical grey matter (CGM) volume reduction of 471 mm2 than Low a3/ a2 group (p<.001). High a3/2 group showed a similar but less marked pattern (160 mm2) of cortical thinning when compared to Middle a3/a2 group (p<.001). Moreover, high a3/2 group had wider cortical thinning than other groups, mapped to the Supramarginal and Precuneus bilaterally. No significant cortical thickness difference was found between Middle and Low a3/a2 groups. Conclusion: High EEG alpha3/alpha2 ratio was associated with impairment of temporo-parietal cortical brain in MCI subjects. The combination of EEG alpha3/alpha2 power ratio and cortical thickness measure could be useful for identifying individuals at risk for progression to AD dementia and may be of value in clinical context.

Secretory leukocyte protease inhibitor protein regulates the penetrance of frontotemporal lobar degeneration in progranulin mutation carriers.

Abstract: The discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases leading to dementia has brought renewed interest in progranulin and its functions in the central nervous system. Full length progranulin is preserved from cleavage by secretory leukocyte protease inhibitor (SLPI), one of the smallest serine protease inhibitor circulating in plasma. Herein, we investigated the relationship between circulating SLPI and progranulin in affected and unaffected subjects belonging to 26 Italian pedigrees carrying GRN null mutations. In GRN null mutation carriers, we demonstrated: i) an increase of circulating SLPI levels in affected subjects; ii) an age-related upregulation of the serine-protease inhibitor in response to lifetime progranulin shortage; and iii) a delay in the age of onset in subjects with the highest SLPI protein levels. The study of SLPI and its relation to progranulin suggests the existence of unexpected molecular players in progranulin-associated neurodegeneration.