Sara Mazzucco

Increased Cerebral Arterial Pulsatility in Patients With Leukoaraiosis: Arterial Stiffness Enhances Transmission of Aortic Pulsatility

Background and Purpose— Arterial stiffening reduces damping of the arterial waveform and hence increases pulsatility of cerebral blood flow, potentially damaging small vessels. In the absence of previous studies in patients with recent transient ischemic attack or stroke, we determined the associations between leukoaraiosis and aortic and middle cerebral artery stiffness and pulsatility. Methods— Patients were recruited from the Oxford Vascular Study within 6 weeks of a transient ischemic attack or minor stroke. Leukoaraiosis was categorized on MRI by 2 independent observers with the Fazekas and age-related white matter change scales. Middle cerebral artery (MCA) stiffness (transit time) and pulsatility (Goslings index: MCA-PI) were measured with transcranial ultrasound and aortic pulse wave velocity and aortic systolic, diastolic, and pulse pressure with applanation tonometry (Sphygmocor). Results— In 100 patients, MCA-PI was significantly greater in patients with leukoaraiosis (0.91 versus 0.73, P<0.0001). Severity of leukoaraiosis was associated with MCA-PI and aortic pulse wave velocity (Fazekas: &khgr;2=0.39, MCA-PI P=0.01, aortic pulse wave velocity P=0.06; age-related white matter change: &khgr;2=0.38, MCA-PI P=0.015; aortic pulse wave velocity P=0.026) for periventricular and deep white matter lesions independent of aortic systolic blood pressure, diastolic blood pressure, and pulse pressure and MCA transit time with MCA-PI independent of age. In a multivariate model (r2=0.68, P<0.0001), MCA-PI was independently associated with aortic pulse wave velocity (P=0.016) and aortic pulse pressure (P<0.0001) and inversely associated with aortic diastolic blood pressure (P<0.0001) and MCA transit time (P=0.001). Conclusions— MCA pulsatility was the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and MCA stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis.

Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP–HHT syndrome†

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP–HHT was described that is also caused by mutations in SMAD4. Although both JP and JP–HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP–HHT patients were clustered in the COOH‐terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre‐symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP–HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP–HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP–HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP–HHT and monitored accordingly.

Cerebral Amyloidoses: Molecular Pathways and Therapeutic Challenges

Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are sporadic and genetic neurodegenerative conditions characterized by brain accumulation and deposition of protein aggregates. In AD, the key pathogenic event is linked to the formation of a 4-kDa amyloid beta (Abeta) peptide, generated by sequential cleavages of the amyloid precursor protein (APP). In CJD and other prion diseases, the process is initiated by conformational changes of the cellular prion protein, or PrP(C), into a beta-sheet rich isoform, named PrP(Sc), which acquires protease-resistance and detergent insolubility. Once generated, Abeta and PrP(Sc) are highly prone to misassembly under thermodynamically favourable oligomeric forms and protofibril/fibril structures. The variety of physicochemical states exhibited by Abeta and PrP(Sc) is accounted for by distinct molecular forms with different amino and/or carboxyl termini and alternative conformations. Unlike Abeta, PrP(Sc) is also infectious, and this feature poses public health concerns, as in the case of iatrogenic and variant CJD (vCJD). Several lines of evidence suggest that Abeta and PrP(Sc) are the main factors responsible for death of selected neuronal populations in brains of AD and prion diseases victims. Therefore, in addition to symptomatic treatment of dementia, therapeutic efforts are currently aimed at testing the efficacy of disease-modifying, anti-amyloid therapies. Experimental and clinical therapeutic interventions include passive and active immunization against amyloidogenic peptides, non immunological strategies, as well as drugs enhancing the nonamyloidogenic protein processing. In this review, we focus on molecular mechanisms of AD and prion diseases, and on novel treatment approaches.

Antipsychotic Drugs and Cerebrovascular Events in Elderly Patients with Dementia: A Systematic Review

Recently, Canadian, US and European health regulatory agencies issued warnings about an increased risk of stroke and death in elderly patients with dementia receiving atypical antipsychotics. Assessing both randomised and non-randomised evidence, this systematic review found conflicting findings, particularly for risperidone. More research is needed to better inform clinical practice.

Upregulated Expression of Toll-like Receptor 4 in Peripheral Blood of Ischaemic Stroke Patients Correlates with Cyclooxygenase 2 Expression

OBJECTIVES An inflammatory process following stroke in human brains and systemic inflammatory responses after stroke in humans have been reported by numerous investigators. The aim of the study was to investigate if genes involved in the cyclooxygenase 2 (COX-2) pathway are upregulated at peripheral level in patients after transient ischaemic attack (TIA) and stroke. DESIGN OF STUDY Blood samples were obtained from two groups of patients undergoing carotid endarterectomy. The first group included 25 patients who presented TIA or ischaemic stroke. The second group included 35 patients who had an asymptomatic internal carotid artery stenosis. Total RNA was isolated and the expression of Toll-like Receptor 4 (TLR4), COX-2, membrane-associated Prostaglandin E synthase (mPGES-1), Prostaglandin E₂ receptors (EP3 and EP4) was analysed by real time RT-PCR. RESULTS Expression of COX-2 and TLR4 were significantly increased in symptomatic patients (p < 0.001). Correlation analysis showed that TLR4 expression significantly correlated with COX-2 expression (R = 0.65; p < 0.01) in ischaemic stroke patients. This correlation was not observed in TIA and asymptomatic patients. CONCLUSIONS Our results suggest that the peripheral mechanism of inflammatory injury after stroke may be mediated by TLR4 through a COX-2-dependent pathway.

Computational Identification of Phospho-Tyrosine Sub-Networks Related to Acanthocyte Generation in Neuroacanthocytosis

Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks by identifying all the interactomic shortest paths linking Xk and chorein to the corresponding set of proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of Xk and chorein on phosphorylated proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc.

Ataxia in posterior circulation stroke: Clinical-MRI correlations.

OBJECTIVE Ataxia is characterized clinically by four signs (gait and limb ataxia, dysarthria and nystagmus). Although ataxia has been described in posterior circulation (PC) stroke series, there are no prospective studies that have investigated a possible differential role of the cerebellum or its input/outputs in causing ataxia. METHODS Ataxia was semi-quantified according to the International Cooperative Ataxia Rating Scale (ICARS) in 92 consecutive patients with acute PC stroke. Four topographical patterns based on magnetic resonance imaging (MRI) findings were identified: picaCH pattern (posterior inferior cerebellar artery infarct); scaCH pattern (superior cerebellar artery infarct); CH/CP pattern (infarct involving both the cerebellum and the brainstem cerebellar pathways); and CP pattern (infarct involving the brainstem cerebellar pathways). RESULTS Gait ataxia was present in 95.7%, limb ataxia in 76.1%, dysarthria in 56.5% and nystagmus in 65.2% of patients. Gait ataxia frequency did not differ between the patterns, but was significantly more severe in the CH/CP pattern than in either picaCH (P=0.0059) or CP (P=0.0065) pattern. Limb ataxia was significantly less frequent (P<0.001) and less severe (P<0.001) in picaCH pattern than other patterns. Dysarthria was less frequent in picaCH pattern than in other patterns (P=0.018) and less severe than in scaCH (P=0.0043) or CP (P=0.0047) pattern. No differences in nystagmus frequency or severity were observed across all four patterns. CONCLUSION In PC stroke gait ataxia was almost always present, regardless of the lesion site. Limb ataxia and dysarthria were less frequent in the picaCH pattern, whereas nystagmus, when present, did not differ among the topographical patterns.

Autonomic dysfunction in mild cognitive impairment: A transcranial Doppler study

Anzola GP, Galluzzi S, Mazzucco S, Frisoni GB. Autonomic dysfunction in mild cognitive impairment: a transcranial Doppler study.
Acta Neurol Scand: 2011: 124: 403–409.
© 2011 John Wiley & Sons A/S.

Paradoxical brain embolism in a young man with isolated pulmonary arteriovenous fistula

We herein report a case of ischemic stroke due to paradoxical brain embolism in a young man, a trumpet player. Extensive diagnostic investigations revealed the presence of an isolated pulmonary arteriovenous fistula as the only risk factor for stroke. The peculiarity of this case is the early onset of neurological symptoms in the absence of Hereditary Hemorrhagic Teleangiectasia. The Authors suppose the repeated Valsalva maneuvers as a possible factor promoting fistula enlargement and symptoms development.

A model of multi-disciplinary approach to the diagnosis and treatment of young patients with cryptogenic stroke and patent foramen ovale.

BACKGROUND Treatment of patent foramen ovale in young patients with stroke is not supported by robust scientific evidence. In clinical practice, a pragmatic approach is needed to guide such therapeutic decisions. This study aims at standardising the diagnostic pathway for stroke patients younger than 55 years of age with a patent foramen ovale; elaborating a therapeutic algorithm; discussing every case in regular interdisciplinary counselling meeting; and setting up a follow-up schedule to assess clinical outcomes. METHODS This is a cohort study on the effect of a standardised treatment of stroke patients with a patent foramen ovale. The primary endpoints include occurrence of recurrent ischaemic events, major bleeding, and device-related complications. The secondary endpoints include drug- or procedure-related side effects, persistence of right-to-left shunt, and persistent cardiac arrhythmia of new onset. RESULTS A total of 103 patients have been enrolled. In all, 51 patients underwent percutaneous atrial septal repair; of these, one had minor post-procedural bleeding. At 12 months, 25% of this group of patients showed a latent I grade shunt, one patient a latent II degree shunt, and none had a persistent shunt. The remaining 52 patients were addressed to medical therapy; one of them experienced stroke recurrences while on medical therapy. CONCLUSIONS This model of implementation of available evidence to clinical practice via a group-based, multi-disciplinary counselling provides a shared and coherent decision pathway and yielded a very low rate of recurrent events and therapy-related complications. This approach could be replicated in specific protocols for other complex or neglected clinical problems.