Publications by authors named "Lorenzo Pinessi"

89 Publications

ATXN2 intermediate repeat expansions influence the clinical phenotype in frontotemporal dementia.

Neurobiol Aging 2019 01 22;73:231.e7-231.e9. Epub 2018 Sep 22.

Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy; Neurology 1, AOU Città della Salute e della Scienza di Torino, Torino, Italy.

Common genetic risk factors are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Intermediate repeat expansions at the Ataxin-2 locus (ATXN2) are a risk factor for ALS and influence the phenotype. We assessed whether ATXN2 is a risk factor for FTD or modify clinical features in a data set of Italian patients. Three hundred sixty-eight unrelated FTD cases and 342 controls were enrolled. The frequency of intermediate CAG repeats in ATXN2 gene was not different comparing patients and controls. CAG repeats were interrupted by CAA in all patients carrying intermediate repeats. Interestingly, patients with an increased number of CAG repeats had an earlier onset of the disease than those without expansions (p = 0.011), and presented more frequently with parkinsonism (p = 0.010), and psychotic symptoms (p = 0.013) at disease onset. Our study does not support a major role of ATXN2 intermediate CAG expansions in predisposing to FTD but suggests that ATXN2 may act as a phenotype modifier.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.09.009DOI Listing
January 2019

Migraine: Genetic Variants and Clinical Phenotypes.

Curr Med Chem 2019 ;26(34):6207-6221

Headache Center, Neurology I, Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy.

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.
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http://dx.doi.org/10.2174/0929867325666180719120215DOI Listing
December 2019

Noninvasive Vagal Nerve Stimulation in Chronic Migraine with Medication Overuse Headache.

Pain Med 2018 12;19(12):2575-2577

Neurology I, Headache Center, Department of Neuroscience "Rita Levi Montalcini," University of Torino, Torino, Italy.

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http://dx.doi.org/10.1093/pm/pny084DOI Listing
December 2018

Subclinical hypothyroidism is associated with migraine: A case-control study.

Cephalalgia 2019 01 22;39(1):15-20. Epub 2018 Apr 22.

2 Endocrinology, Diabetes and Metabolic Disease Unit, A.O. Ordine Mauriziano di Torino, Torino, Italy.

Background: Recent studies suggested a potential association between both overt and subclinical hypothyroidism and migraine. Aims of this study were to estimate the comorbidity of migraine in patients with subclinical hypothyroidism and to evaluate associated clinical characteristics.

Methods: Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine.

Results: The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs. 13%, p < 0.001; OR 5.80; 95% CI = 3.35-10.34). Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls ( p < 0.001 and p = 0.010, respectively). Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine. Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine ( p = 0.005).

Conclusions: Our data suggest that migraine is more frequent in patients with subclinical hypothyroidism in respect to controls. Further studies are needed in order to confirm this association.
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http://dx.doi.org/10.1177/0333102418769917DOI Listing
January 2019

Corrigendum to "Neural correlates of reduced awareness in instrumental activities of daily living in frontotemporal dementia" [Exp. Gerontol. 83 (2016) 158-164].

Exp Gerontol 2017 10 17;96:164-165. Epub 2017 Jun 17.

Centro Interdipartimentale di Studi Avanzati in Neuroscienze, National Institute of Turin (NIT), Regione Gonzole 10, 10043 Orbassano, Italy; Neurology I and Alzheimer Evaluation Unit, Department of Neuroscience, Via Cherasco 15, 10126 Turin, Italy.

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http://dx.doi.org/10.1016/j.exger.2017.05.022DOI Listing
October 2017

Recent advances in the molecular genetics of frontotemporal lobar degeneration.

Funct Neurol 2017 Jan/Mar;32(1):7-16

The term frontotemporal lobar degeneration (FTLD) describes a spectrum of neurodegenerative disorders associated with deposition of misfolded proteins in the frontal and temporal lobes. Up to 40% of FTLD patients reports a family history of neurodegeneration, and approximately 1/3 of familial cases shows an autosomal dominant pattern of inheritance of the phenotype. Over the past two decades, several causative and susceptibility genes for FTLD have been discovered, supporting the notion that genetic factors are important contributors to the disease processes. Genetic variants in three genes, MAPT, GRN and C9orf72, account for about half of familial FTLD cases. In addition, rare defects in the CHMP2B, VCP, TARDBP, SQSTM1, FUS, UBQLN, OPTN, TREM2, CHCHD10 and TBK1 genes have been described. Additional genes are expected to be found in near future. The purpose of this review is to describe recent advances in the molecular genetics of the FTLD spectrum and to discuss implications for genetic counseling.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505533PMC
http://dx.doi.org/10.11138/fneur/2017.32.1.007DOI Listing
May 2017

O057. Altered plasma adipokines concentrations in chronic migraine.

J Headache Pain 2015 Dec;16(Suppl 1):A56

Department of Neuroscience "Rita Levi Montalcini", University of Torino, Turin, Italy.

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http://dx.doi.org/10.1186/1129-2377-16-S1-A56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759114PMC
December 2015

P055. Prevalence of migraine in subclinical hypothyroidism: a case-control study.

J Headache Pain 2015 Dec;16(Suppl 1):A81

Division of Endocrinology Diabetes and Metabolism, Department of Medicine, A.O. Ordine Mauriziano, Turin, Italy.

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http://dx.doi.org/10.1186/1129-2377-16-S1-A81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759091PMC
December 2015

P014. Migraine and hypnosis.

J Headache Pain 2015 Dec;16(Suppl 1):A86

Headache Centre, Neurology I, Department of Neurosciences, University Hospital City of Health and Sciences, Turin, Italy.

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http://dx.doi.org/10.1186/1129-2377-16-S1-A86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759359PMC
December 2015

Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia.

J Alzheimers Dis 2017 ;56(4):1271-1278

Department of Clinical and Experimental Science, Neurology Unit, University of Brescia, Italy.

In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.
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http://dx.doi.org/10.3233/JAD-160949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178215PMC
February 2018

Genetic analysis of CHCHD2 and CHCHD10 in Italian patients with Parkinson's disease.

Neurobiol Aging 2017 05 5;53:193.e7-193.e8. Epub 2017 Jan 5.

Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy; Neurology 1, Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza di Torino, Torino, Italy.

In recent years, CHCHD2 and CHCHD10 mutations were reported to be associated with a broad spectrum of neurodegenerative diseases, including Parkinson's disease (PD), although with conflicting results in different populations. The present study aimed to evaluate CHCHD2 and CHCHD10 coding variants in Italian patients with PD. All the coding regions and flanking intronic splice sites of CHCHD2 and CHCHD10 were sequenced. None of our 119 PD cases carried CHCHD2 mutations, whereas 1 sporadic PD patient showed the Pro34Ser substitution in CHCHD10. Our data suggest that CHCHD2 and CHCDH10 mutations are not a relevant cause of PD in Italian population.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.12.027DOI Listing
May 2017

Successful use of bevacizumab in an adult primary diffuse leptomeningeal glioneuronal tumor.

J Neurosurg Sci 2018 Apr 27;62(2):229-232. Epub 2016 Sep 27.

Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy.

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http://dx.doi.org/10.23736/S0390-5616.16.03804-2DOI Listing
April 2018

Investigating the role of adipokines in chronic migraine.

Cephalalgia 2017 Oct 22;37(11):1067-1073. Epub 2016 Aug 22.

1 Neurology I - Headache Center, Rita Levi Montalcini Department of Neuroscience, University of Torino, Italy.

Background and aims Adiponectin, leptin, and resistin are adipocyte-derived secretory factors involved in endothelial function, weight, inflammation, and insulin resistance. Recent studies suggested a role for adipokines in episodic migraine as mediators of inflammatory processes. The aim of this study was to investigate plasma concentrations of adiponectin, leptin, and resistin in patients with chronic migraine. Materials and methods Twenty-seven chronic migraineurs (20 females, 7 males; mean age 49.0 ± 9.0 yrs) and 37 healthy controls (23 females, 14 males; mean age 49.8 ± 15.0 yrs) were selected for the study. Fasting plasmatic levels of total adiponectin, leptin, and resistin were measured using ELISA kits during a pain-free period. Fasting glucose, insulin, total and HDL-cholesterol, triglycerides, and ESR were also determined. Results Serum levels of adiponectin and resistin were significantly increased in chronic migraineurs in comparison with controls ( p = 0.001 and p = 0.032, respectively). After correction for BMI, sex and age, leptin levels were significantly increased in chronic migraineurs ( p = 0.007). A positive correlation between leptin concentrations and both indices of insulin resistance and markers of inflammation was found. Discussion Our data suggest that adiponectin and resistin are altered in non-obese chronic migraineurs. Further studies are needed to elucidate the neurobiological mechanisms underlying adipokine dysfunction in migraine.
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http://dx.doi.org/10.1177/0333102416665871DOI Listing
October 2017

Neural correlates of reduced awareness in instrumental activities of daily living in frontotemporal dementia.

Exp Gerontol 2016 10 14;83:158-64. Epub 2016 Aug 14.

Centro Interdipartimentale di Studi Avanzati in Neuroscienze, National Institute of Turin (NIT), Regione Gonzole 10, 10043 Orbassano, Italy; Neurology I and Alzheimer Evaluation Unit, Department of Neuroscience, Via Cherasco 15, 10126 Turin, Italy.

A decline in instrumental activities of daily living has been described as the earliest functional deficit in patients with neurodegenerative disease. It embraces specific competencies such as: "recalling the date and telephone calls, orienting to new places, remembering the location of objects at home, understanding conversation and the plot of a movie, keeping belongings in order, doing mental calculations and handling money, remembering appointments and shopping lists and performing clerical work". Since changes in instrumental daily living activities are one of the descriptors of behavioural-variant frontotemporal dementia, we decided to investigate the neural correlates of a reduced awareness in this specific domain in twenty-three consecutive behavioural-variant frontotemporal dementia patients. Gray matter volume changes associated with a reduced awareness for the instrumental domain, assessed using a validated caregiver-patient discrepancy questionnaire, were examined. Interestingly, we found disabilities in instrumental daily living activities and a reduced awareness of these to be related to medial prefrontal cortex atrophy, where the mid-cingulate cortices, dorsal anterior insula and cuneous play an important role. Importantly, if the executive system does not function correctly, the comparator mechanism of action self-monitoring does not detect mismatches between the current and previous performance states stored in the personal database, and produces a reduced awareness for the instrumental domain.
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http://dx.doi.org/10.1016/j.exger.2016.08.008DOI Listing
October 2016

Reversible disconnection syndrome in a case of acute tumefactive demyelinating lesion: a PET study.

Neurol Sci 2016 Dec 25;37(12):2019-2023. Epub 2016 Jul 25.

Department of Neuro-Oncology, University and A.O.U. City of Health and Science, Turin, Italy.

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http://dx.doi.org/10.1007/s10072-016-2675-xDOI Listing
December 2016

Cognitive and Neurophysiological Effects of Non-invasive Brain Stimulation in Stroke Patients after Motor Rehabilitation.

Front Behav Neurosci 2016 24;10:135. Epub 2016 Jun 24.

Physical Medicine and Rehabilitation, University of Turin Turin, Italy.

The primary aim of this study was to evaluate and compare the effectiveness of two specific Non-Invasive Brain Stimulation (NIBS) paradigms, the repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial Direct Current Stimulation (tDCS), in the upper limb rehabilitation of patients with stroke. Short and long term outcomes (after 3 and 6 months, respectively) were evaluated. We measured, at multiple time points, the manual dexterity using a validated clinical scale (ARAT), electroencephalography auditory event related potentials, and neuropsychological performances in patients with chronic stroke of middle severity. Thirty four patients were enrolled and randomized. The intervention group was treated with a NIBS protocol longer than usual, applying a second cycle of stimulation, after a washout period, using different techniques in the two cycles (rTMS/tDCS). We compared the results with a control group treated with sham stimulation. We split the data analysis into three studies. In this first study we examined if a cumulative effect was clinically visible. In the second study we compared the effects of the two techniques. In the third study we explored if patients with minor cognitive impairment have most benefit from the treatment and if cognitive and motor outcomes were correlated. We found that the impairment in some cognitive domains cannot be considered an exclusion criterion for rehabilitation with NIBS. ERP improved, related to cognitive and attentional processes after stimulation on the motor cortex, but transitorily. This effect could be linked to the restoration of hemispheric balance or by the effects of distant connections. In our study the effects of the two NIBS were comparable, with some advantages using tDCS vs. rTMS in stroke rehabilitation. Finally we found that more than one cycle (2-4 weeks), spaced out by washout periods, should be used, only in responder patients, to obtain clinical relevant results.
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http://dx.doi.org/10.3389/fnbeh.2016.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919333PMC
July 2016

Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38).

Parkinsonism Relat Disord 2016 07 27;28:80-6. Epub 2016 Apr 27.

Ospedale Regionale Microcitemie, ASL 8, Cagliari, Italy.

Introduction: SCA38 (MIM 611805) caused by mutations within the ELOVL5 gene, which encodes an enzyme involved in the synthesis of long-chain fatty acids with a high and specific expression in Purkinje cells, has recently been identified.

Objective: The present study was aimed at describing the clinical and neuroimaging features, and the natural history of SCA38.

Methods: We extended our clinical and brain neuroimaging data on SCA38 including 21 cases from three Italian families. All had the ELOVL5 c.689G > T (p.Gly230Val) missense mutation.

Results: Age at disease onset was in the fourth decade of life. The presenting features were nystagmus (100% of cases) and slowly progressive gait ataxia (95%). Frequent signs and symptoms included pes cavus (82%) and hyposmia (76%); rarer symptoms were hearing loss (33%) and anxiety disorder (33%). The disease progressed with cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and ophtalmoparesis followed in the later stages by ophtalmoplegia. Peripheral nervous system involvement was present in the last phase of disease with sensory loss. Dementia or extrapyramidal signs were not detected. Significant loss of abilities of daily living was reported only after 20 years of the disease. Brain imaging documented cerebellar atrophy with sparing of cerebral cortex and no white matter disease.

Conclusions: SCA38 is a rare form of inherited ataxia with characteristic clinical features, including pes cavus and hyposmia, that may guide genetic screening and prompt diagnosis in light of possible future therapeutic interventions.
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http://dx.doi.org/10.1016/j.parkreldis.2016.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925464PMC
July 2016

PRNP P39L Variant is a Rare Cause of Frontotemporal Dementia in Italian Population.

J Alzheimers Dis 2016 ;50(2):353-7

Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%).
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http://dx.doi.org/10.3233/JAD-150863DOI Listing
November 2016

The rehabilitative effects on written language of a combined language and parietal dual-tDCS treatment in a stroke case.

Neuropsychol Rehabil 2017 Sep 22;27(6):904-918. Epub 2015 Oct 22.

c Neuroscience Department , University of Turin , Turin , Italy.

In this paper we report the effect of a combined transcranial direct current stimulation (tDCS) and speech language therapy on linguistic deficits following left brain damage in a stroke case. We show that simultaneous electrical excitatory stimulation to the left and inhibitory stimulation to the right parietal regions (dual-tDCS) affected writing and reading rehabilitation, enhancing speech therapy outcomes. The results of a comparison with healthy controls showed that application of dual-tDCS could improve, in particular, sub-lexical transcoding and, specifically, the reading of non-words with increasing length and complexity. Positive repercussions on patient's quality of functional communication were also ascertained. Significant changes were also found in other language and cognitive tasks not directly treated (comprehension and constructive apraxia).
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http://dx.doi.org/10.1080/09602011.2015.1103759DOI Listing
September 2017

Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis.

Mult Scler 2016 07 7;22(8):1007-12. Epub 2015 Oct 7.

Multiple Sclerosis Center, Department of Neuroscience, City of Health and Science University Hospital of Turin, Italy.

Background: Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in multiple sclerosis (MS) brains by macrophages and microglia.

Methods: In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers.

Results: We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01).

Conclusion: GRN genetic polymorphisms likely influence disease course and relapse recovery in MS.
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http://dx.doi.org/10.1177/1352458515610646DOI Listing
July 2016

Paroxysmal perceptual alteration in a schizophrenic patient treated with paliperidone: A case report.

Ann Clin Psychiatry 2015 Aug;27(3):223-4

Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy Department of Neuroscience and Mental Health, A.O.U. Città della Salute e della Scienza, Torino, Italy. E-mail:

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August 2015

Molecularly based management of gliomas in clinical practice.

Neurol Sci 2015 Sep 21;36(9):1551-7. Epub 2015 Jul 21.

Department of Neuro-Oncology, University and City of Health and Science Hospital, Via Cherasco 15, 10126, Turin, Italy,

Histological subtyping and grading of malignancy are the cornerstone of the present World Health Organization (WHO) Classification of CNS tumors. However, among diffuse gliomas of the adult, patients with histologically identical tumors may have different outcomes. As the genomic analysis of these tumors has progressed, it has become clear that specific molecular features transcend histologically defined variants, and may become markers of prognostic and/or predictive value. At the present time, the number of molecular biomarkers with confirmed clinical relevance (MGMT promoter methylation, 1p/19q codeletion, IDH1/2 mutations) remains limited, but new technologies will hopefully provide new candidates requiring rigorous validation in well-designed clinical trials.
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http://dx.doi.org/10.1007/s10072-015-2332-9DOI Listing
September 2015

Neurofunctional Signature of Hyperfamiliarity for Unknown Faces.

PLoS One 2015 8;10(7):e0129970. Epub 2015 Jul 8.

Department of Psychology, University of Torino, Torino, Italy; Department of Medical and Clinical Psychology and CoRPS-Center of Research on Psychology in Somatic diseases-Tilburg University, Tilburg, The Netherlands; Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.

Hyperfamiliarity for unknown faces is a rare selective disorder that consists of the disturbing and abnormal feeling of familiarity for unknown faces, while recognition of known faces is normal. In one such patient we investigated with a multimodal neuroimaging design the hitherto undescribed neural signature associated with hyperfamiliarity feelings. Behaviorally, signal detection methods revealed that the patient's discrimination sensitivity between familiar and unfamiliar faces was significantly lower than that of matched controls, and her response criterion for familiarity decisions was significantly more liberal. At the neural level, while morphometric analysis and single-photon emission CT (SPECT) showed the atrophy and hypofunctioning of the left temporal regions, functional magnetic resonance imaging (fMRI) revealed that hyperfamiliarity feelings were selectively associated to enhanced activity in the right medial and inferior temporal cortices. We therefore characterize the neurofunctional signature of hyperfamiliarity for unknown faces as related to the loss of coordinated activity between the complementary face processing functions of the left and right temporal lobes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129970PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495981PMC
April 2016

A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia.

Neurobiol Aging 2015 Oct 12;36(10):2904.e13-26. Epub 2015 Jun 12.

Department of Neurology, IRCCS Multimedica, Milan, Italy.

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values ∼10(-7) and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706156PMC
October 2015

Double-Cone Coil TMS Stimulation of the Medial Cortex Inhibits Central Pain Habituation.

PLoS One 2015 5;10(6):e0128765. Epub 2015 Jun 5.

Neuroscience Department, University of Turin, Turin, Italy; Neuroscience Department, AOU Citta della Salute e della Scienza (Presidio Molinette), Turin, Italy.

Objective: The aim of this study was to investigate whether Transcranial Magnetic Stimulation (TMS) applied over the medial line of the scalp affects the subjective perception of continuous pain induced by means of electric stimulation. In addition, we wanted to identify the point of stimulation where this effect was maximum.

Methods: Superficial electrical stimulation was used to induce continuous pain on the dominant hand. At the beginning of the experiment we reached a pain rating of 5 on an 11-point numeric rating scale (NRS; 0 = no pain and 10 = maximum tolerable pain) for each subject by setting individually the current intensity. The TMS (five pulses at increasing intensities) was applied on 5 equidistant points (one per session) over the medial line of the scalp in 13 healthy volunteers using a double-cone coil to stimulate underlying parts of the brain cortex. In every experimental session the painful stimulation lasted 45 minutes, during which pain and distress intensities NRS were recorded continuously. We calculated the effect of adaptation and the immediate effect of the TMS stimulation for all locations. Additionally, an ALE (Activation Likelihood Estimation) meta-analysis was performed to compare our results with the neuroimaging literature on subjective pain rating.

Results: TMS stimulation temporarily decreased the pain ratings, and pain adaptation was suppressed when applying the TMS over the FCz site on the scalp. No effect was found for distress ratings.

Conclusions: The present data suggest that the medial cortex in proximity of the cingulated gyrus has a causal role in adaptation mechanisms and in processing ongoing pain and subjective sensation of pain intensity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128765PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457929PMC
February 2016

A review of the recent advances in neuroimaging of frontotemporal lobar degeneration.

J Neurosurg Sci 2017 04 20;61(2):180-192. Epub 2015 May 20.

Neuropsychophysiology and Imaging Lab (LabNI), Department of Neuroscience, University of Turin, Turin, Italy -

Introduction: The term "frontotemporal lobar degeneration" (FTLD) includes a large set of neurodegenerative diseases, which are heterogeneous in their genetic, pathologic and clinical aspects. This review will focus on the most recent contribution of neuroimaging tools on the diagnosis, characterization and pathogenesis of FTLD.

Evidence Acquisition: Scopus, Ovid, PubMed and MEDLINE were searched for articles published from January 2012 up to December 2014. Searches were limited to articles published in English. Frontotemporal lobar degeneration as a key word was always in the search queries in combination with logic AND, and at least one other key word.

Evidence Synthesis: We found 91 papers of interest and reviewed their contents, finding in particular 4 major topics: the contribution of neuroimaging on the differential diagnosis; patients' functional characterization; new neuroimaging tools under development and pre-symptomatic genetic forms.

Conclusions: Neuroimaging techniques have shown to be useful supporting tools in diagnosis, even if not always determinant to reach a conclusive decision, and quite important to identify phenocopies. At the moment, there is not a neuroimaging biomarker that could track the progressive course of dementias and the effect of therapies, but it is possible that in the future Diffusion Tensor Imaging and molecular imaging could fill this void. Monitoring the evolution of the pathology in vivo for at least 5 years is essential, and this would only be possible in a large multicenter study; asymptomatic forms would require even longer observation periods.
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http://dx.doi.org/10.23736/S0390-5616.16.03281-1DOI Listing
April 2017

Brain correlates of alexithymia in eating disorders: A voxel-based morphometry study.

Psychiatry Clin Neurosci 2015 Nov 26;69(11):708-16. Epub 2015 Jun 26.

Department of Neuroscience, University of Turin, Turin, Italy.

Aims: Alexithymia is a personality trait that consists of difficulty in identifying and acknowledging one's own and others' feelings. Recent studies reported that alexithymia is present in both anorexia (AN) and bulimia nervosa (BN). Brain morphological studies on healthy subjects showed that alexithymia correlates with several brain regions involved in emotions processing. The aim of this study was to investigate the anatomical correlates of alexithymia in AN and BN.

Methods: We performed a voxel-based morphometry study on 21 patients with AN and 18 with BN. Seventeen healthy subjects were used as a control group. Alexithymia, depression and anxiety were assessed with self-administered questionnaires and correlated to gray matter (GM) density in each group.

Results: In BN, alexithymia was correlated with the GM of the parietal lobe, in particular of the right angular gyrus. The correlation was predominantly linked with Difficulty Describing Feelings. In AN, we did not find correlations between GM and alexithymia.

Conclusions: In BN, our results support the hypothesis that this trait may represent a relevant pathogenic or maintenance factor that contributes to relational difficulties, present in this pathology. In AN, the lack of correlation between GM volume and alexithymia may be influenced by atrophy in several brain regions that in turn can be, as previously reported, a consequence of caloric restriction. Also, the nature of alexithymia may be different from that of BN and controls and this trait could be secondary to a psychopathologic process specific to AN.
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http://dx.doi.org/10.1111/pcn.12318DOI Listing
November 2015

An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2.

BMC Med Genet 2015 Mar 19;16:16. Epub 2015 Mar 19.

Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy.

Background: Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases.

Methods: We describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene.

Results: Exome sequencing identified a homozygous c.6292C > T (p.Arg2098*) mutation in SETX and a heterozygous c.346G > A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy. Pathogenicity prediction and a yeast-functional assay suggested p.Gly116Arg impaired m-AAA (ATPases associated with various cellular activities) complex function.

Conclusions: Exome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C > T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant). We suggest that variant phenotypes may be due to the combined effect of different mutated genes associated to ataxia or related disorders, that will become more apparent as the costs of exome sequencing progressively will reduce, amplifying its diagnostics use, and meanwhile proposing significant challenges in the interpretation of the data.
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http://dx.doi.org/10.1186/s12881-015-0159-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422141PMC
March 2015