Showing papers by "Giuliano Binetti published in 2014"

Frontotemporal dementia and its subtypes: a genome-wide association study

Abstract: Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes— MAPT , GRN , and C9orf72 —have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p −8 ) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p −8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 −8 ; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10 −9 ; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10 −8 , 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38 / CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 −7 ; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis . Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Abstract: Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease.

Abstract: Objective Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up. Methods The study included 42 MCI converters and 99 stable MCI subjects. We assessed levels of copper, ceruloplasmin, non-Cp copper, iron, transferrin, ferritin, and APOE genotype. A multiple Cox regression analysis—with age, sex, baseline Mini-Mental State Examination, APOE4, iron, non-Cp copper, transferrin, ferritin, hypercholesterolemia, and hypertension as covariates—was applied to predict the conversion from MCI to AD. Results Among the evaluated parameters, the only significant predictor of conversion to AD was non-Cp copper (hazard ratio = 1.23, 95% confidence interval = 1.03–1.47, p = 0.022); for each additional micromole per liter unit (μmol/l) of non-Cp copper, the hazard increased by ∼20%. Subjects with non-Cp copper levels >1.6μmol/l had a hazard conversion rate (50% of conversion in 4 years) that was ∼3× higher than those with values ≤1.6μmol/l (<20% in 4 years). The rate of conversion was similar between APOE4 carriers and noncarriers (p = 0.321), indicating that the non-Cp copper association was independent of APOE4. Interpretation Non-Cp copper appears to predict conversion from MCI to AD. These results encourage healthy life style choices and dietary intervention to modify this risk. ANN NEUROL 2014;75:574–580

Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers

Abstract: Background To investigate the patterns of brain atrophy, white matter (WM) tract changes, and functional connectivity (FC) abnormalities in asymptomatic granulin ( GRN ) mutation carriers. Methods Ten cognitively normal subjects (five mutation carriers, GRN +; years to estimated disease onset: 12 ± 7; five mutation noncarriers, GRN −) underwent a clinical and imaging (structural, diffusion tensor, and resting-state functional magnetic resonance imaging) assessment. Brain atrophy was measured with cortical thickness analysis, WM abnormalities with tract-based spatial statistics, and FC with independent component analysis. Results GRN + showed smaller cortical thickness than GRN − in the right orbitofrontal and precentral gyrus and left rostral middle frontal gyrus. WM tracts abnormalities were limited to increased axial diffusivity in the right cingulum, superior longitudinal fasciculus, and corticospinal tract. There were no differences in FC of resting-state networks. Conclusion Brain atrophy and WM tract abnormalities in frontal-parietal circuits can be detected at least a decade before the estimated symptom onset in asymptomatic mutation carriers.

Rotigotine is safe and efficacious in Atypical Parkinsonism Syndromes induced by both α-synucleinopathy and tauopathy

Abstract: Transdermal rotigotine (RTG) is a non-ergot dopamine agonist (D3>D2>D1), and is indicated for use in early and advanced Parkinson’s disease (PD). RTG patch has many potential advantages due to the immediacy of onset of the therapeutic effect. Of note, intestinal absorption is not necessary and drug delivery is constant, thereby avoiding drug peaks and helping patient compliance. In turn, transdermal RTG seems a suitable candidate in the treatment of atypical Parkinsonian disorders (APS). Fifty-one subjects with a diagnosis of APS were treated with transdermal RTG. The diagnoses were: Parkinson’s disease with dementia, multiple system atrophy Parkinsonian type, multiple system atrophy cerebellar type, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, and frontotemporal dementia with Parkinsonism. Patients were evaluated by the Unified Parkinson’s Disease Rating Scale (UPDRS; part III), Neuropsychiatric Inventory (NPI), and mini–mental state examination (MMSE) and all adverse events (AEs) were recorded. Patients treated with RTG showed an overall decrease of UPDRS III scores without increasing behavioral disturbances. Main AEs were hypotension, nausea, vomiting, drowsiness, tachycardia, and dystonia. On the whole, 15 patients were affected by AEs and seven patients suspended RTG treatment due to AEs. The results show that transdermal RTG is effective with a good tolerability profile. RTG patch could be a good therapeutic tool in patients with APS.

Behavioral and Neurophysiological Effects of Transdermal Rotigotine in Atypical Parkinsonism

Abstract: Effective therapies for the so-called atypical parkinsonian disorders (APS) such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) are not available. Dopamine agonists are not often used in APS because of inefficacy and, in a minority of case, their side effects, like dyskinesias, impairment of extrapiramidal symptoms or the appearance of psychosis and REM sleep behavioral disorders. (RBD). Transdermal rotigotine (RTG) is a non-ergot dopamine agonist indicated for use in early and advanced Parkinson’s disease with a good tolerability and safety. Moreover, its action on a wide range of dopamine receptors, D1, D2, D3, unlike other dopamine agonists, could make it a good option in APS, where a massive dopamine cell loss is documented. In this pilot, observational open-label study we evaluate the efficacy and tolerability of RTG in patients affected by APS. 32 subjects with diagnosis of APS were treated with transdermal RTG. APS diagnosis was: multiple system atrophy parkinsonian type (MSA-P), multiple system atrophy cerebellar type (MSA-C), PSP, CBS. Patients were evaluated by UPDRS-III, NPI, MMSE at baseline and after 6, 12 and 18 months. The titration schedule was maintained very flexible, searching the major clinical effect and the minor possible adverse events at each visit. Adverse events were recorded. APS patients treated with RTG show a overall decrease of UPDRS III scores without increasing behavioral disturbances. Only 3 patients were dropped out of the study. Main adverse events were hypotension, nausea, vomiting, drowsiness, tachycardia. The EEG power spectra analysis shows a decrease of theta and an increase of low alpha power. In conclusion, transdermal RTG seems to be effective and well tolerated in APS patients.

Comparison of the effects of transdermal and oral rivastigmine on cognitive function and EEG markers in patients with Alzheimer’s disease

Abstract: Background: Alzheimer's disease (AD) is the most common cause of dementia in older patients. Rivastigmine (RV, Exelon®, Novartis), a reversible cholinesterase inhibitor, improves clinical manifestations of AD and may enhance ACh-modulated electroencephalogram (EEG) alpha frequency. This pilot study aimed to determine the effects of two formulations of RV (transdermal patch [TV-RDP] and oral capsules [TV-CP]) on alpha frequency, in particular the posterior dominant rhythm, and cognitive function (assessed by the Mini-Mental State Examination [MMSE]) in patients with AD. Methods: Subjects with AD were assigned to receive either RV-TDP 10 cm2 or RV-CP 12 mg/day. All patients underwent EEG recordings at the beginning and end of the 18-month study period using P3, P4, O1 and O2 electrodes, each at high (10.5–13.0 Hz) and low (8.0–10.5 Hz) frequency. MMSE scores were determined at the start of the study (T0) and at three successive 6-month intervals (T1, T2 and T3). Results: RV-TDP administration (n=10) maintained cognitive function as evidenced by stable MMSE scores from baseline to 18 months (21.07 ± 2.4 to 21.2 ± 3.1) compared with a decrease in MMSE score with RV-CP (n=10) over 18 months (18.3 ± 3.6 to 13.6 ± 5.06 [adjusted for covariates p=0.006]). MMSE scores were significantly different between treatment groups from 6 months (p=0.04). RV-TDP also increased the spectral power of alpha waves in the posterior region measured with electrode P3 in a significantly great percentage of patients than TV-CP from baseline to 18 months; 80% versus 30%, respectively (p=0.025 [χ2 test]). Conclusion: RV-TDP was associated with a greater proportion of patients with increased posterior region alpha wave spectral power and significantly higher cognitive function at 18 months, compared with RV-CP treatment. Our findings suggest that RV-TDP provides an effective long-term management option in patients with AD compared with oral RV-CP. This study is a pilot, open-label study with a

EEG Upper/Low Alpha Frequency Power Ratio and the Impulsive Disorders Network in Subjects with Mild Cognitive Impairment.

Abstract: The ventral striatum-nucleus accumbens network has been associated with impulsive behavior in subjects with early cognitive impairment; in Alzheimer's disease (AD) modifications of basal ganglia have been also demonstrated. Moreover, the increase of EEG alpha3/alpha2 frequency power ratio has been investigated as EEG marker in subjects with mild cognitive impairment (MCI) who will develop AD. In the present study we have detected the relationship between upper alpha/low alpha ferquency power ratio and specific gray matter (GM) changes in the basal ganglia in subjects with MCI. Electroencefalographic (EEG) recording and high resolution 3D magnetic resonance imaging (MRI) were taken in 74 MCI subjects. In each subject the alpha3/alpha2 EEG frequency power ratio was estimated as EEG biomarker. Three groups were obtained according to increasing tertiles values of the biomarker. Through the Voxel Based Morphometry (VBM) technique, GM density differences between groups were evaluated. Results show that subjects with lower a3/a2 and middle a3/a2 ratio ratio showed greater gray matter reduction in the Nucleus Accumbens and the head of Caudate Nucleus as compared to subjects with higher a3/a2 ratio. Our study indicates that the a3/a2 frequency power ratio was associated with increase of grey matter density inside the impulsivity network of MCI patients more likely develop AD.