Leonardo Pantoni

Is type 2 diabetes related to leukoaraiosis? an updated review

A significantly increased interest has been dedicated to the study of the effects of diabetes mellitus (DM) on the brain. DM is associated with an increased risk of stroke and cognitive decline. In patients with DM, neuroimaging discloses with high‐frequency structural changes, such as cerebral atrophy, infarcts and white matter lesions, also called leukoaraiosis (LA), an expression of small vessel disease. A previous review showed a relation between DM and both cerebral atrophy and lacunar infarcts, while the question about the relation between DM and LA remained unanswered. In this review, we provide an update on data on this last association. In the reviewed studies, we examined the presence of DM, other disease characteristics, such as duration and complications, and laboratory markers of the disease such as blood glycated hemoglobin (HbA1c), insulin resistance, insulin concentrations and their association with LA. About 40% of the reviewed studies reported a statistically significant association between DM and LA. Long‐standing DM and a poor glycemic control were associated with severe LA. Studies using innovative MRI techniques, such as diffusion tensor imaging (DTI), reported a significant association between microstructural white matter alterations and DM. This review highlights more firmly than previously reported the existence of a relation between DM and both presence and severity of LA. These results are possibly due to more sensitive and advanced imaging techniques recently used to study the extent of LA. However, because of the heterogeneous methodology used in the reviewed studies, a definitive conclusion cannot be drawn.

Advances in Stroke 2017

For stroke rehabilitation and recovery, 2017 was a year of reviews and research advances. Reviews included all aspects of poststroke rehabilitation and recovery. Cognitive rehabilitation for memory deficits was effective for memory improvements in the short term, but not in the long term.1 Circuit class therapy could improve mobility after stroke in a clinically meaningful way, even after 12 months poststroke.2 Electromechanical-assisted training for walking was most beneficial for subacute stroke survivors who were not ambulatory.3 Repetitive task training was effective regardless of the amount of task practice, type of intervention, or time since stroke.4 Physical activity training could positively affect poststroke cognition with small-to-moderate treatment effects that were apparent even in the chronic stroke phase.5 In all cases, more research was required to improve the quality of the findings, and a review of poststroke fatigue reported that the overall quality of the research was poor.6 Discovery research provided more insight into basic aspects of stroke rehabilitation and recovery. Stradecki-Cohan et al7 studied Sprague–Dawley rats subjected to 5 to 6 days of no (0 m/min), mild (6 m/min), moderate (10 m/min), or heavy (15–18 m/min) treadmill exercise 3 to 4 days poststroke and demonstrated that moderate exercise enhanced cognitive function for 1 week after exercise completion, independent of changes in physical fitness. Chang et al8 demonstrated that the number of Met alleles in brain-derived neurotrophic factor genotypes and corticospinal tract (CST) functional integrity may be independent predictors of upper extremity motor outcome 3 months poststroke. Tu et al9 found that concentrations of FABP4 (fatty acid–binding protein 4), an intracellular lipid chaperone involved in coordination of lipid transportation and atherogenesis, were a novel independent prognostic marker for poor functional outcome and mortality 3 months poststroke. Imaging of the CST also played a …

Functional magnetic resonance imaging with encoding task in patients with mild cognitive impairment and different severity of leukoaraiosis

Leukoaraiosis is one of the main contributors to mild cognitive impairment due to vascular damage (vascular MCI, VMCI), whose pathophysiology has not been fully elucidated yet. We aimed to shed light on such issue using functional MRI (fMRI). Sixteen patients with VMCI were enrolled and compared with twenty-five patients with MCI but without significant vascular damage (non-vascular MCI, NVMCI) and with fifteen healthy controls (HC). They all underwent fMRI with incidental verbal learning paradigm, using a 3T scanner. Differently from cases with NVMCI (versus HC), VMCI patients presented a higher BOLD activation in the right parieto-occipital cortex and a lower activation in the left superior and middle frontal gyri, anterior cingulum and in left fronto-opercular area when compared to HC. Cortical activation evaluated by fMRI may reflect specific patterns of damage and attempt of compensation in patients with MCI and different severity of leukoaraiosis.

Personality traits in migraineurs: a case-control study by personality inventory for DSM-5 (PID-5)

The prevalence of psychological symptoms in migraineurs is greater than in the general population, andmigraineurs aremore vulnerable to psychopathology, probably for a common pathogenetic mechanism. The prevalence of depression and anxiety is increased among migraineurs [1], and a lot of evidence in literature suggests a strong correlation between pathological personality and migraine [2]. The role of the psychological factors related with migraine has led to the hypothesis of a proper Bmigraine-associated personality.^ With respect to episodic migraineurs, chronic migraine patients are thought to be more prone to depressed mood, anxiety disorders, and drug overuse, with a high frequency of neuroticism and dependent personality profile. Migraineurs seem more prone to intrinsic defensive mechanisms and to respond to stressors with an increased internal tension [3]. The migraine patients use coping strategies characterized by the development of physical symptoms, social isolation, and preoccupation with stress. These evidences were obtained along many decades with various psychometric tools, frequently very different from one another and some of these tools are now considered inadequate. The dimensional valuation of personality traits proposed in DSM-5 is considered nowadays the most appropriate modality to study the personality disorders. The first aim of this study is to evaluate comparatively the presence of maladaptive/pathological personality traits in a migraineurs population compared to a population of nonheadache sufferers, using an updated tool: the Personality Inventory for DSM-5 (PID-5). A secondary objective of the study is to investigate a possible relationship between the maladaptive traits of personality and migraine characteristics such as migraine-associated symptoms, disease duration, and frequency of headaches. The study included 124 patients (102 women, 22 men) with a diagnosis of migraine with and/or without aura, according to ICHD-III criteria, and 77 controls (63 women, 14 men) without any type of primary headache or with very occasional headache attacks (< 1/year). The investigation about the maladaptive traits of personality was made with the PID-5, a psychometric survey that considers the five main traits and the 25 facets of the maladaptive trait empiric model of DSM-5. The PID-5 is a 220-item self-rated personality trait assessment scale for adults aged 18 and older. The five domains are (in brackets the facet scales contributing primarily to each domain): Negative Affect (Emotional Lability, Anxiousness, Separation Insecurity), Detachment (Withdrawal, Anhedonia, Intimacy Avoidance), Antagonism (Manipulativeness, Deceitfulness, Grandiosity), Disinhibition (Irresponsibility, Impulsivity, Distractibility), Psychoticism (Unusual Beliefs and Experiences, Eccentricity, Perceptual Dysregulation). The 25 personality trait facets assessed are Anhedonia, Anxiousness, Attention Seeking, Callousness, Deceitfulness, Depressivity, Distractibility, Eccentricity, Emotional Lability, Grandiosity, Hostility, Impulsivity, Intimacy Avoidance, Irresponsibility, Manipulativeness, Perceptual Dysregulation, Perseveration, Restricted Affectivity, Rigid Perfectionism, Risk Taking, Separation Insecurity, Submissiveness, Suspiciousness, Unusual Beliefs and Experiences, and Withdrawal. The data extracted from the questionnaires were analyzed with χ test, correlation test, Student’s t test, and logistic regression. The populations of cases and controls were comparable for age and gender. The PID-5 scores were higher in cases in the facets of Anhedonia (p < 0.001), Anxiousness (p = 0.007), Unusual Beliefs and Experiences (p = 0.03), Depressivity (p = 0.001), Perceptual Dysregulation (p = 0.02), Intimacy Avoidance (p < 0,001), Hostility (p < 0.001), Perseveration (p = 0.04), Withdrawal (p = 0.01), the most of which are also * Carlo Lovati carlo.lovati@tiscali.it

The brain effect of the migraine attack: an ASL MRI study of the cerebral perfusion during a migraine attack

The migrainous brain experiences, during the attack, a sequence of sudden and reversible modifications of which often there are not direct demonstrations. One of the few phenomena that we are able to describe in detail is cortical spreading depression (CSD), which is usually considered as involved only in the starting phase of the migraine attack with aura. The aim of this study is to investigate the brain effect of the migraine attack without aura, focusing on hemodynamic variations, measuring the focal perfusion and the global arterial inflow in migraine patients during an attack, and comparing these parameters with migraine patients during the intercritical phase and with controls. We included migraine patients enrolled at the L. Sacco Hospital Bheadache center,^ keeping on the enrolment until reaching seven patients that presented a migraine attack during the MR acquisition. A total of 30 migraine patients (15 chronic and 15 episodic migraineurs) and 15 controls, comparable by age, were enrolled. All the subjects were female, in order to eliminate the possible bias coming from gender difference. The subjects went through a brain MR using a 1.5Tesla scanner (Siemens MagnetomAvanto, Erlangen, Germany), with a protocol including also angio-MR and arterial spin labeling (ASL) sequences, at IRCCS Don Carlo Gnocchi Foundation in Milan. Pseudo-continuous ASL (PCASL) with single-shot 3D Gradient and Spin Echo (GRASE) readout sequences were used to study the brain perfusion. A total of 60 tag images and 60 control images were obtained with 5 different post labeling delays (PLD), with 12 repetitions for each PLD. The comparison of the local perfusion values between patients during the attack, patients in the interictal phase, and controls was obtained with the (ANCOVA) voxel-wise analysis, with age correction. This analysis was done on CBF maps normalized in the MNI space by a non-parametric method of permutation (5000 iterations)with the randomize tool of FSL (https://fsl.fmrib.ox.ac. uk/fsl/). A p value corrected for multiple comparisons with a family wise error (FWE) < 0.05 was considered significant. The voxels that resulted significantly different between the groups were mapped with the Harvard-Oxford atlas.

Resolution of unilateral upper limb action tremor after surgical treatment of a contralateral frontoparietal arachnoid cyst

PurposeArachnoid cysts (ACs) are cerebrospinal fluid-filled sacs. Although ACs are a frequent finding on neuroimaging, most remain asymptomatic during lifetime.Case reportWe report a very rare case of a 62-year-old female patient presenting with a tremor due to a giant arachnoid cyst, which completely resolved after cyst-peritoneal shunting.

May migraine attack response to triptans be a predictor of the efficacy of Onabotulinum toxin-A prophylaxis?

In relationship with the frequency of headache episodes, migraine may be labeled as episodic (< 15 headache days per month) or chronic (≥ 15 days/month for more than 3 months), with the latter being a very disabling condition. In the past decades, the so-feared Onabotulinum toxin-A (BoNT-A) has conversely acquired the role of a versatile therapeutic substance, used in an increasing number of pathological situations, including chronic headache and more precisely for the prophylaxis of chronic migraine. The efficacy of BoNT-A prophylactic activity is well proved but the latency between the first inoculation and the possible reduction of frequency and intensity of migraine may last from 3 to 9 months. In order to try to reduce this useless latency and to improve the patient selection for this treatment, a series of possible predictive markers have been investigated [1]. A series of biological elements involved in the pathophysiology of migraine have been recognized as targets of the BoNT-A action in preventing headache recurrence and manifestations. The most relevant physiopatological elements of migraine related with BoNT-A activity are calcitonin generelated peptide (CGRP) and TRP channels. These evidences allowed to identify some biochemical, neurophysiological [2] laser-evoked potential responses [3], peculiar brain MRI and fMRI, and characteristics and clinical manifestations. Unfortunately, as of now, these predictors are still not sufficiently validated or available for the clinical practice. Triptans are the most specific drugs available for the treatment of migraine attacks. Their mechanism of action involves both a 5-HT1B-mediated vasoconstrictive action and an inhibition of CGRP release, with a subsequent reduction of the activation of trigeminal nociceptors. Therefore, triptans and BoNT-A share a common mechanism of action, that is, the inhibition of CGRP transmission. On this basis, we aimed to evaluate a possible relationship between the efficacy of triptans and the response to a prophylaxis with BoNT-A. A total of 44 chronic migraine patients according to ICHD III diagnostic criteria, refractory to conventional pharmacological prophylaxis and consecutively treated with BoNT-A were included. We considered refractory all the patients without any significant positive beneficial response to all common prophylactic treatments including flunarizine, beta-blockers, topiramate, and amitriptyline at correct dosage and for a reasonable treatment duration. We included patients after at least four consecutive treatments with 170–195 BoNT-A units injected according to the PREEMPT protocol. With regard to BoNT-A, patients were labeled as Bgood BoNT-A responders^ when they reported a reduction of at least 50% in migraine frequency, Bmoderate BoNT-A responders^ when they related a reduction of migraine frequency lower than 50% or a reduction of pain intensity from severe to mildmoderate in the larger part of migraine attacks with the elimination of disabling attacks; Bnon BoNT-A responders^ did not report any significant change in their migraine. We defined Bgood triptan responders^ those patients in whom one or more triptans were able to stop the near totality of migraine attacks without relapses; Bmoderate triptan responders^ the ones with an inconstant (less than 50% of attacks) effect of at least one triptan in the control of migraine attacks and with the necessity to use a rescue therapy in more than half of migraine episodes. We labeled as Bnon triptan responders^ patients in whom none of triptans resulted able to modify migraine attacks. The χ test was used to compare the frequency of BoNT-A responders among triptans responders versus non-responders. * Carlo Lovati carlo.lovati@tiscali.it

Notch3 protein expression in skin fibroblasts from CADASIL patients

AIM CADASIL is an inherited cerebrovascular disease caused by mutations in the NOTCH3 gene. Notch signaling is involved in a broad spectrum of function, from the cell proliferation to apoptosis. Thus far, because the molecular mechanism underlying the pathological alterations remains unclear and taking into account that fibroblasts contribute to the integrity of the vasculature, our aims was to establish whether fibroblasts, in subjects carrying different NOTCH3 mutations, show abnormalities in the protein expression. METHODS We performed the investigation on skin fibroblasts in culture obtained from three CADASIL patients and normal subjects. The patients were genetically characterized, and carried a p.R61W, a p.C174T, and p.R103X, mutation respectively. Notch3 expression was first evaluated on fibroblasts by immunofluorescence analysis, then western blot on cellular extract was utilized to validate the immunofluorescence results. RESULTS The Notch3 immunoreactivity was clearly detected along the cellular body and in the cellular nuclei of the control fibroblasts. We observed a marked, statistically significant, reduction of the fluorescence immunoreactivity in the fibroblasts from patient with the classical C174T cysteine mutation and a less pronounced reduction in the other two subjects samples with respect to the normal controls. These data were confirmed by the immunoblot analysis. CONCLUSIONS Our results show that the investigated three NOTCH3 mutations are associated with a reduction of the levels of Notch3 expression in vitro. Because the smooth muscle cells appear to be predominantly involved in this cerebrovascular disease, our result, despite the limitation of the sample size examinated, clearly suggest that also fibroblasts, directly involved in making the vascular basal lamina and in maintaining the vascular integrity, may play an important role in the mechanism responsible for the disease.

Reperfusion Injury after ischemic Stroke Study (RISKS): single-centre (Florence, Italy), prospective observational protocol study

Introduction Treatments aiming at reperfusion of the acutely ischaemic brain tissue may result futile or even detrimental because of the so-called reperfusion injury. The processes contributing to reperfusion injury involve a number of factors, ranging from blood–brain barrier (BBB) disruption to circulating biomarkers. Our aim is to evaluate the relative effect of imaging and circulating biomarkers in relation to reperfusion injury. Methods and analysis Observational hospital-based study that will include 140 patients who had ischaemic stroke, treated with systemic thrombolysis, endovascular treatment or both. BBB disruption will be assessed with CT perfusion (CTP) before treatment, and levels of a large panel of biomarkers will be measured before intervention and after 24 hours. Relevant outcomes will include: (1) reperfusion injury, defined as radiologically relevant haemorrhagic transformation at 24 hours and (2) clinical status 3 months after the index stroke. We will investigate the separate and combined effect of pretreatment BBB disruption and circulating biomarkers on reperfusion injury and clinical status at 3 months. Study protocol is registered at http://www.clinicaltrials.gov (ClinicalTrials.gov ID: NCT03041753). Ethics and dissemination The study protocol has been approved by ethics committee of the Azienda Ospedaliero Universitaria Careggi (Università degli Studi di Firenze). Informed consent is obtained by each patient at time of enrolment or deferred when the participant lacks the capacity to provide consent during the acute phase. Researchers interested in testing hypotheses with the data are encouraged to contact the corresponding author. Results from the study will be disseminated at national and international conferences and in medical thesis. Trial registration number NCT03041753.

Cerebral small vessel disease and systemic arteriopathy in intracranial arterial dolichoectasia patients

To investigate clinical and demographic characteristics of patients with intracranial arterial dolichoectasia (IADE) and describe the possible coexistence of cerebral small vessel disease (SVD) and systemic arteriopathy.