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Background and objectives Cerebral microbleeds (CMBs) are a neuroimaging expression of small vessel disease (SVD). We investigated in a cohort of SVD patients with mild cognitive impairment (MCI): 1) the reliability of the Microbleed Anatomical Rating Scale (MARS); 2) the burden and location of CMBs and their association with cognitive performances, independent of other clinical and neuroimaging features. Methods Patients underwent clinical, neuropsychological (4 cognitive domains), and MRI assessments. CMBs were assessed by three raters. Results Out of the 152 patients (57.2% males; mean age ± SD: 75.5 ± 6.7 years) with gradient-echo (GRE) sequences, 41 (27%) had at least one CMB. Inter-rater agreement for number and location of CMBs ranged from good to very good [multi-rater Fleiss kappa (95%CI): 0.70–0.95]. Lacunar infarcts and some clinical variables (e.g., hypertension and physical activity) were associated with CMBs in specific regions. Total number of CMBs and of those in deep and lobar regions were associated with attention/executive and fluency domains. Discussion MARS is a reliable instrument to assess CMBs in SVD patients with MCI. Nearly one third of these patients had at least one CMB. Total CMBs burden was associated with attention/executive functions and fluency domains impairment, lacunar infarcts, and with some potentially modifiable risk factors.

Background and objective Vascular cognitive impairment may have a selective neuropsychological profile. We developed a battery for assessing mild cognitive impairment (MCI) in patients with small vessel disease (SVD), its applicability, and psychometric properties. Methods Among those proposed by the 2006 NINDS-CSN Consensus Conference, we selected tests for which norms based on healthy Italians and equivalent scores methodology were available. Confirmatory factor analysis was applied to ascertain the fit of the theoretically assumed dimensions to empirical data and to derive each cognitive dimension compound measures. Results The entire battery was applied to 146 out of a cohort of 201 patients with MCI and SVD. Most tests showed good applicability. Fifty-five patients, who were older and cognitively more impaired, proved unable to complete the Trail Making Test part B, the Rey-Osterrieth Complex Figure, and the Stroop test, and were excluded from the analysis. Among the remaining patients, Mini-Mental State Examination proved largely normal, while Rey-Osterrieth Complex Figure, Symbol digit modalities test, and Trail Making Test part B were most frequently abnormal. Confirmatory factor analysis showed a good fit of the 4-factor theoretical model to empirical data. Praxis domain resulted in the highest percentage of abnormal performance (65%), followed by Memory and Attention/EF domains (19% and 15%), and Language (8%). Conclusions Our battery proved to be comprehensive, robust, and applicable. Attention-executive dysfunction and impaired memory and visuo-constructional abilities, were the prominent features. The assessment of the Consensus Conference, that included Trial Making Test, looks poorly applicable to older and cognitively impaired patients.

The term leuko‐araiosis (LA) describes a common chronic affection of the cerebral white matter (WM) in the elderly due to small vessel disease with variable clinical correlates. To explore whether severity of LA entails some adaptive reorganization in the cerebral cortex we evaluated with functional MRI (fMRI) the cortical activation pattern during a simple motor task in 60 subjects with mild cognitive impairment and moderate or severe (moderate‐to‐severe LA group, n = 46) and mild (mild LA group, n = 14) LA extension on visual rating. The microstructural damage associated with LA was measured on diffusion tensor data by computation of the mean diffusivity (MD) of the cerebral WM and by applying tract based spatial statistics (TBSS). Subjects were examined with fMRI during continuous tapping of the right dominant hand with task performance measurement. Moderate‐to‐severe LA group showed hyperactivation of left primary sensorimotor cortex (SM1) and right cerebellum. Regression analyses using the individual median of WM MD as explanatory variable revealed a posterior shift of activation within the left SM1 and hyperactivation of the left SMA and paracentral lobule and of the bilateral cerebellar crus. These data indicate that brain activation is modulated by increasing severity of LA with a local remapping within the SM1 and increased activity in ipsilateral nonprimary sensorimotor cortex and bilateral cerebellum. These potentially adaptive changes as well lack of contralateral cerebral hemisphere hyperactivation are in line with sparing of the U fibers and brainstem and cerebellar WM tracts and the emerging microstructual damage of the corpus callosum revealed by TBSS with increasing severity of LA. Hum Brain Mapp 35:819–830, 2014. © Wiley Periodicals, Inc.

Aims: The DSM-5 introduced the term “major neurocognitive disorders” (NCDs) to replace the previous term “dementia.” However, psychometric and functional definitions of NCDs are missing. We aimed to apply the DSM-5 criteria for diagnosing the transition to NCD to patients with mild cognitive impairment (MCI) and small vessel disease (SVD), and to define clinically significant thresholds for this transition. Methods: The functional and cognitive features of the NCD criteria were evaluated as change from baseline and operationalized according to hierarchically ordered psychometric rules. Results: According to the applied criteria, out of 138 patients, 44 were diagnosed with major NCD (21 with significant cognitive worsening in ≥1 additional cognitive domain), 84 remained stable, and 10 reverted to normal. Single-domain MCI patients were the most likely to revert to normal, and none progressed to major NCD. The amnestic multiple-domain MCI patients had the highest rate of progression to NCD. Conclusion: We provide rules for the DSM-5 criteria for major NCD based on cognitive and functional changes over time, and define psychometric thresholds for clinically significant worsening to be used in longitudinal studies. According to these operationalized criteria, one-third of the MCI patients with SVD progressed to major NCD after 2 years, but only within the multiple-domain subtypes.

// Diego Carrella 1 , Isabella Manni 3 , Barbara Tumaini 1 , Rosanna Dattilo 2 , Federica Papaccio 3 , Margherita Mutarelli 1 , Francesco Sirci 1 , Carla A. Amoreo 4 , Marcella Mottolese 4 , Manuela Iezzi 5 , Laura Ciolli 5 , Valentina Aria 6 , Roberta Bosotti 7 , Antonella Isacchi 7 , Fabrizio Loreni 6 , Alberto Bardelli 8,9 , Vittorio E. Avvedimento 10 , Diego di Bernardo 1,11 and Luca Cardone 3 1 Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy 2 Department of Hematology, Oncology and Molecular Medicine, Biobank Unit, Istituto Superiore di Sanita, Rome, Italy 3 Department of Research, Advanced Diagnostics, and Technological Innovations, Regina Elena National Cancer Institute, Rome, Italy 4 S.C. Anatomia Patologica, Regina Elena National Cancer Institute, Rome, Italy 5 Immuno-Oncology Laboratory, Aging Research Center, G. d’Annunzio University of Chieti, Pescara, Italy 6 Department of Biology, University of Rome Tor Vergata, Rome, Italy 7 Nerviano Medical Sciences SRL, Nerviano, Italy 8 Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy 9 Department of Oncology, University of Torino, Candiolo, Torino, Italy 10 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli “Federico II”, Naples, Italy 11 Department of Electrical Engineering and Information Technology, University of Naples “Federico II”, Naples, Italy Correspondence to: Luca Cardone, email: // Diego di Bernardo, email: // Keywords : oncogenes, PI3K-dependent pathways, gene expression signatures, drugs network, FDA-approved drugs Received : January 03, 2016 Accepted : August 03, 2016 Published : August 16, 2016 Abstract The discovery of inhibitors for oncogenic signalling pathways remains a key focus in modern oncology, based on personalized and targeted therapeutics. Computational drug repurposing via the analysis of FDA-approved drug network is becoming a very effective approach to identify therapeutic opportunities in cancer and other human diseases. Given that gene expression signatures can be associated with specific oncogenic mutations, we tested whether a “reverse” oncogene-specific signature might assist in the computational repositioning of inhibitors of oncogenic pathways. As a proof of principle, we focused on oncogenic PI3K-dependent signalling, a molecular pathway frequently driving cancer progression as well as raising resistance to anticancer-targeted therapies. We show that implementation of “reverse” oncogenic PI3K-dependent transcriptional signatures combined with interrogation of drug networks identified inhibitors of PI3K-dependent signalling among FDA-approved compounds. This led to repositioning of Niclosamide (Niclo) and Pyrvinium Pamoate (PP), two anthelmintic drugs, as inhibitors of oncogenic PI3K-dependent signalling. Niclo inhibited phosphorylation of P70S6K, while PP inhibited phosphorylation of AKT and P70S6K, which are downstream targets of PI3K. Anthelmintics inhibited oncogenic PI3K-dependent gene expression and showed a cytostatic effect in vitro and in mouse mammary gland. Lastly, PP inhibited the growth of breast cancer cells harbouring PI3K mutations. Our data indicate that drug repositioning by network analysis of oncogene-specific transcriptional signatures is an efficient strategy for identifying oncogenic pathway inhibitors among FDA-approved compounds. We propose that PP and Niclo should be further investigated as potential therapeutics for the treatment of tumors or diseases carrying the constitutive activation of the PI3K/P70S6K signalling axis.

Introduction Mild cognitive impairment (MCI) prodromic of vascular dementia is expected to have a multidomain profile. Methods In a sample of cerebral small vessel disease (SVD) patients, we assessed MCI subtypes distributions according to different operationalization of Winblad criteria and compared the neuroimaging features of single versus multidomain MCI. We applied three MCI diagnostic scenarios in which the cutoffs for objective impairment and the number of considered neuropsychological tests varied. Results Passing from a liberal to more conservative diagnostic scenarios, of 153 patients, 5% were no longer classified as MCI, amnestic multidomain frequency decreased, and nonamnestic single domain increased. Considering neuroimaging features, severe medial temporal lobe atrophy was more frequent in multidomain compared with single domain. Discussion Operationalizing MCI criteria changes the relative frequency of MCI subtypes. Nonamnestic single domain MCI may be a previously nonrecognized type of MCI associated with SVD.