Roberto Gasparotti

Diffusion tensor imaging and voxel based morphometry study in early progressive supranuclear palsy

Background: A comprehensive characterisation of grey and white matter changes in progressive supranuclear palsy (PSP), the second most common extrapyramidal syndrome after Parkinson disease, is still not available. Objective: To evaluate grey and white matter changes in mild PSP patients by voxel based morphometry (VBM) and diffusion tensor imaging (DTI), respectively. Methods: 14 mild PSP patients and 14 healthy controls entered the study and underwent a clinical and neuropsychological evaluation according with a standardised assessment. Each subject had a structural magnetic resonance imaging (MRI) study. Processing analysis of MRI data was carried out according to optimised VBM and fractional anisotropy was determined. Results: Compared with the controls, in PSP patients VBM analysis showed a significant clusters of reduced grey matter in premotor cortex, frontal operculum, anterior insula, hippocampus, and parahippocampal gyrus, bilaterally. With regard to subcortical brain regions, the pulvinar, dorsomedial and anterior nuclei of the thalamus, and superior and inferior culliculum were affected bilaterally. A bilateral decrease in fractional anisotropy in superior longitudinal fasciculus, anterior part of corpus callosum, arcuate fascicolus, posterior thalamic radiations, and internal capsule, probably involving the cortico-bulbar tracts, was present in PSP patients. Conclusions: These data provide evidence for both grey and white matter degeneration in PSP from the early disease stage. These structural changes suggest that atrophy of cortical and subcortical structures and neurodegeneration of specific fibre tracts contribute to neurological deficits in PSP.

Migraine Mediates the Influence of C677T MTHFR Genotypes on Ischemic Stroke Risk With a Stroke-Subtype Effect

Background and Purpose— The objective was to investigate the role of C677T MTHFR polymorphism in migraine pathogenesis and in the migraine–ischemic stroke pathway. Methods— A first genotype–migraine association study was conducted on 100 patients with migraine with aura (MA), 106 with migraine without aura (MO), and 105 subjects without migraine, which provided evidence in favor of association of the TT677 MTHFR genotype with increased risk of MA compared with both control subjects (OR, 2.48; 95% CI, 1.11 to 5.58) and patients with MO (OR, 2.21; 95% CI, 1.01 to 4.82). Based on these findings, mediational models of the genotype–migraine–stroke pathway were fitted on a group of 106 patients with spontaneous cervical artery dissection, 227 young patients whose ischemic stroke was unrelated to a spontaneous cervical artery dissection (noncervical artery dissection), and 187 control subjects, and a genotype–migraine partial mediation model was selected. Results— Both migraine and the TT genotype were more strongly associated to the subgroup of patients with spontaneous cervical artery dissection (OR, 4.06; 95% CI, 1.63 to 10.02 for MA; OR, 5.45; 95% CI, 3.03 to 9.79 for MO; OR, 2.87; 95% CI, 1.45 to 5.68 for TT genotype) than to the subgroup of patients with noncervical artery dissection ischemic stroke (OR, 2.22; 95% CI, 1.00 to 4.96 for MA; OR, 1.81; 95% CI, 1.02 to 3.22 for TT genotype) as compared with controls. Conclusions— Migraine may act as mediator in the methylenetetrahydrofolate reductase–ischemic stroke pathway with a more prominent effect in the subgroup of patients with spontaneous artery dissection.

Transcranial Doppler Sonography and Magnetic Resonance Angiography in the Assessment of Collateral Hemispheric Flow in Patients With Carotid Artery Disease

BACKGROUND AND PURPOSE The aim of this investigation was to compare the respective efficacy of transcranial Doppler sonography (TCD) and magnetic resonance angiography (MRA) for the assessment of intracranial hemodynamics in patients with extracranial occlusion or severe stenosis of the internal carotid artery (ICA). METHODS Twenty-five patients with unilateral ICA occlusion (n = 20) or tight stenosis (n = 5) demonstrated by duplex scanning or angiography were studied with both TCD and MRA. Three-dimensional time-of-flight MRA was used for the evaluation of extracranial-intracranial ICAs. Collateralization through the circle of Willis was investigated by means of selective two-dimensional MRA with presaturation of the carotid siphon, ophthalmic artery, or basilar artery. TCD was performed according to published standards: Anterior, middle, and posterior cerebral arteries were insonated through the temporal window, and carotid siphon and ophthalmic artery were assessed through a transorbital approach. Collateralization through the anterior circle of Willis was assumed if anterior cerebral artery flow was reversed, through the external carotid artery if ophthalmic artery flow was reversed, and through the basilar artery if the ratio of ipsilateral to contralateral posterior cerebral artery velocity was greater than 50%. TCD and MRA were performed by different investigators unaware of the results obtained with the other technique. RESULTS In every case time-of-flight MRA demonstrated the ICA occlusion or stenosis. There was an excellent correlation (kappa = 0.64) between TCD and MRA in assessing the hemodynamic contribution of the anterior part of the circle of Willis, whereas MRA was unable to detect the anastomotic pathway of the ophthalmic artery (kappa = 0.32). The contribution of the posterior communicating artery was difficult to assess with both techniques, but in three cases only MRA showed unequivocal evidence of collateralization. In three cases of middle cerebral artery stenosis TCD was superior to MRA in demonstrating the patency of the vessel. CONCLUSIONS TCD and MRA should be considered complementary techniques. Combining the findings of both examinations may help to better understand the changes in intracranial hemodynamics produced by extracranial carotid occlusion. The contribution of the ophthalmic pathway, although important for the intraorbital structures, is probably of limited functional significance to the hemispheric blood supply.

Short-lasting unilateral neuralgiform headache attacks with tearing and conjunctival injection: the first "symptomatic" case?

A 36-year-old man was suffering from brief, unilateral and short-lasting pain attacks always associated with marked homolateral tearing and conjunctival injection, both presenting in a cluster fashion. An arteriovenous malformation was subsequently discovered in the homolateral cerebellopontine angle. The clinical picture shares similarities with both cluster headache and trigeminal neuralgia, although it can not be accurately placed with either of these forms. Patients with similar symptoms have previously been described in detail, and on the basis of these few descriptions a new syndrome “short-lasting” unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhoea has been postulated. Assuming the validity of this syndrome as an entity, this case is in all probability its first “symptomatic” example. Careful evaluation of the varieties of cluster headache and trigeminal neuralgia, and the reporting of similar new cases as they arise are necessary to establish the nosologic boundaries of this syndrome.

Perfusion CT in patients with acute ischemic stroke treated with intra-arterial thrombolysis: predictive value of infarct core size on clinical outcome.

BACKGROUND AND PURPOSE: A potential role of perfusion CT (PCT) in selecting patients with stroke for reperfusion therapies has been recently advocated. The purpose of the study was to assess the reliability of PCT in predicting clinical outcome of patients with acute ischemic stroke treated with intra-arterial thrombolysis (IAT). MATERIALS AND METHODS: Twenty-seven patients with acute hemispheric ischemic stroke were investigated with PCT and treated with IAT between 3 and 6 hours of stroke onset. The infarct core was outlined on cerebral blood volume (CBV) maps by using accepted viability thresholds. The penumbra was defined as time-to-peak (TTP)-CBV mismatch. Clinical outcome was assessed by modified Rankin Scale (mRS) scores at 3 months and dichotomized into favorable (mRS score, 0–2) and unfavorable (mRS score, 3–6). Data were retrospectively analyzed by multiple regression to identify predictors of clinical outcome among the following variables: age, sex, National Institutes of Health Stroke Scale score, serum glucose level, thrombolytic agent, infarct core and mismatch size, collateral circulation, time to recanalization, and recanalization rate after IAT. RESULTS: Patients with favorable outcome had smaller cores (P = .03), increased mismatch ratios (P = .03), smaller final infarct sizes (P < .01), higher recanalization rates (P = .03), and reduced infarct growth rates (P < .01), compared with patients with unfavorable outcome. The core size was the strongest predictor of clinical outcome in an “all subset” model search (P = .01; 0.96 point increase in mRS score per any increment of 1 SD; 95% confidence interval, +0.17 to +1.75). CONCLUSIONS: PCT is a reliable tool for the identification of irreversibly damaged brain tissue and for the prediction of clinical outcome of patients with acute stroke treated with IAT.

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

Granulin (GRN) mutations have been identified as a major cause of frontotemporal lobar degeneration (FTLD) by haploinsufficiency mechanism, although their effects on brain tissue dysfunction and damage still remain to be clarified. In this study, we investigated the pattern of neuroimaging abnormalities in FTLD patients, carriers and noncarriers of GRN Thr272fs mutation, and in presymptomatic carriers. We assessed regional gray matter (GM) atrophy, and resting (RS)-functional magnetic resonance imaging (fMRI). The functional connectivity maps of the salience (SN) and the default mode (DMN) networks were considered. Frontotemporal gray matter atrophy was found in all FTLD patients (more remarkably in those GRN Thr272fs carriers), but not in presymptomatic carriers. Functional connectivity within the SN was reduced in all FTLD patients (again more remarkably in those mutation carriers), while it was enhanced in the DMN. Conversely, presymptomatic carriers showed increased connectivity in the SN, with no changes in the DMN. Our findings suggest that compensatory mechanisms of brain plasticity are present in GRN-related FTLD, but with different patterns at a preclinical and symptomatic disease stage.

Brain Magnetic Resonance Imaging Structural Changes in a Pedigree of Asymptomatic Progranulin Mutation Carriers

Mutations in the progranulin (PGRN) gene have been recently demonstrated as a cause of frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusion (FTD-U). Neuropathologic, clinical, and neuroimaging features associated with PGRN mutations have been carefully described. No studies on asymptomatic subjects carrying pathogenetic PGRN mutations are available yet. These would be crucial for establishing the timing of brain changes and bringing new insight into disease pathogenesis and disease course. The aim of this study was to evaluate structural brain morphology using diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) in asymptomatic carriers of PGRN delCACT mutation belonging to a four-generation FTLD pedigree (mean age, 37.0 +/- 12.0). The evaluation of the family proband presenting with progressive nonfluent aphasia at 53 years of age, revealed left frontotemporal hypoperfusion and atrophy. VBM analysis of gray and white matter reductions revealed no differences between asymptomatic carriers (n = 7) and controls (n = 15), and between no-carriers (n = 10) and controls (p < 0.001). DTI analysis revealed a reduction in fractional anisotropy in healthy PGRN mutation carriers in the left uncinate fasciculus, connecting the orbito-frontal regions to the temporal pole, and in the left inferior occipitofrontal fasciculus, connecting the parieto-occipital cortex to the dorsolateral frontal cortex (p < 0.001). No significant difference in fractional anisotropy between no-carriers and controls was found. Our data indicate loss of white matter integrity as an early preclinical feature in familial FTD that might antedate the onset of specific neurologic features. Alteration of fiber tracts within the perisylvian language network might represent the early hallmark of subsequent aphasia onset. The study of other pedigrees of asymptomatic PGRN mutation carriers is warranted.

White Matter Changes in Corticobasal Degeneration Syndrome and Correlation With Limb Apraxia

BACKGROUND Data on white matter changes in corticobasal degeneration syndrome (CBDS) are not yet available, whereas cortical gray matter loss is a feature of this condition. The structural abnormalities related to a key feature of CBDS (limb apraxia) are unknown. OBJECTIVES To measure selective structural changes in early CBDS using diffusion tensor imaging and voxel-based morphometry and to evaluate the structural correlates of limb apraxia. DESIGN Patient and control group comparison. SETTING Referral center for dementia and movement disorders. PARTICIPANTS Twenty patients with CBDS and 21 matched control subjects. INTERVENTIONS Clinical and standardized neuropsychological evaluations, including assessment of limb apraxia. MAIN OUTCOME MEASURES Gray and white matter changes in early CBDS. RESULTS Diffusion tensor imaging revealed decreases in fractional anisotropy in the long frontoparietal connecting tracts, the intraparietal associative fibers, and the corpus callosum. Fractional anisotropy was also reduced in the sensorimotor projections of the cortical hand areas. Voxel-based morphometry showed a prevalent gray matter reduction in the left hemisphere (in the inferior frontal and premotor cortices, parietal operculum, superotemporal gyrus, and hippocampus). The pulvinar, bilaterally, and the right cerebellar cortex also showed atrophy. Limb apraxia correlated with parietal atrophy and with fractional anisotropy reductions in the parietofrontal associative fibers (P < .01). The limb-kinetic component of apraxia correlated with reduction of hand sensorimotor connecting fibers. CONCLUSIONS The present integrative approach to in vivo structural anatomy combines hodologic imaging, describing patterns of white matter connections between cortical areas, with neuropsychological data. This provides new evidence of gray matter and fiber tract abnormalities in early-phase disease and contributes to clarifying the neural basis of apraxia in CBDS.

Subcortical and deep cortical atrophy in Frontotemporal Lobar Degeneration

Though neuroimaging, pathology and pathophysiology suggest a subcortical and deep cortical involvement in Frontotemporal Lobar Degeneration (FTLD), no studies have comprehensively assessed the associated gray matter (GM) volume changes. We measured caudate, putamen, thalamus, and amygdala GM volume using probabilistic a-priori regions of interest (ROIs) in 53 early FTLD patients (38 behavioral variant FTD [bvFTD], 9 Semantic Dementia [SD], 6 Progressive Non-Fluent Aphasia [PNFA]), and 25 age-matched healthy controls (HC). ANOVA showed significant (P<0.001) main effect of diagnosis, and significant interactions for diagnosis and region, and diagnosis and hemisphere. Post-hoc comparisons with HC showed bilateral GM atrophy in the caudate, putamen and thalamus, in bvFTD; a left-confined GM reduction in the amygdala in SD; and bilateral GM atrophy in the caudate and thalamus, and left-sided GM reduction in the putamen and amygdala in PNFA. Correlation analyses suggested an association between GM volumes and language, psychomotor speed and behavioral disturbances. This study showed a widespread involvement of subcortical and deep cortical GM in early FTLD with patterns specific for clinical entity.

Debunking 7 Myths That Hamper the Realization of Randomized Controlled Trials on Intra-Arterial Thrombolysis for Acute Ischemic Stroke

Background and Purpose— Although intravenous (IV) thrombolysis is the standard treatment for patients with ischemic stroke occurring within 3 hours from symptom onset, a few interventional neuroradiologists have been treating this category of patients by an intra-arterial (IA) route for >25 years. However, evidence is still required to support the clinical feeling that IA treatment, which needs longer time and greater complexity, leads to a better outcome. Therefore, the objective of the present review was to analyze beliefs and myths underlying the selection of patients for IA thrombolysis. Methods and Results— We identified and debunked the following myths on IA thrombolysis: (1) IA thrombolysis works better than IV because it achieves higher recanalization rates; (2) IA thrombolysis works better than IV after the 3-hour window; (3) IA thrombolysis works better than IV in vertebrobasilar stroke; (4) carotid duplex, transcranial doppler, CT angiography, or MRA should be used to screen for major vessel occlusion treatable with IA thrombolysis; (5) to be treated with IA thrombolysis, patients should be selected with diffusion/perfusion MRI; (6) IA thrombolysis should be used as a “rescue” therapy for IV thrombolysis; and (7) the efficacy of IA thrombolysis depends on the thrombolytic agent or the device used. Conclusion— Evidence on acute stroke management with IA thrombolysis is scant. Therefore, neither clinicians nor patients have enough information to make truly informed decisions about the most appropriate treatment. Only randomized controlled trials can clear uncertainties about the possible superiority of IA over IV thrombolysis. Regretfully, case series on IA treatment have limited the organization of such trials and have only favored the spread of myths.