Claudia Altamura

Ceruloplasmin/Transferrin System Is Related to Clinical Status in Acute Stroke

Background and Purpose— In acute stroke, Iron (Fe) may amplify reperfusion injury by catalyzing the conversion of superoxide and hydrogen peroxide into highly reactive radicals. Transferrin (Tf) is the main protein regulating Fe homeostasis, whereas Ceruplasmin (CP) is a circulating ferroxidase enzyme able to oxidize ferrous ions to less toxic ferric forms. This study aims at investigating whether CP, Copper (Cu), Tf, and Fe play a role in the pathophysiology of acute stroke. Methods— We enrolled 35 acute stroke patients and 44 controls. All patients underwent: neurological examination assessed by National Institutes of Health Stroke Scale (NIHSS), ultrasound evaluation of carotid atherosclerosis, brain MRI to quantify ischemic lesion volume and measurement of serum levels of CP, Cu, Tf, Fe, hydro-peroxides, and Total plasmatic antioxidant capacity. Results— In patients, NIHSS scores were associated with Tf (r=−0.48, P=0.004), hydro-peroxides (r=0.34, P=0.046), CP (r=0.43, P=0.012), and lesion volume (r=0.50, P=0.004). Lesion volume was inversely associated with Tf (r=−0.44, P=0.012). CP and hydro-peroxides were also largely related (r=0.81, P<0.001). The model multiple R was 0.57, resulting in a 32.5% of explained NIHSS variance with Tf accounting for 23.4% and CP for 9.1%. Conclusions— CP and Tf levels are representative of clinical status in acute stroke patients. Our findings suggest a protective role of Tf in acute stroke and a possible ambivalent role of CP.

Cerebrovascular reactivity predicts stroke in high-grade carotid artery disease

Objective: To assess the usefulness of transcranial Doppler CO2 reactivity (CO2R) for prediction of ipsilateral ischemic stroke in carotid artery stenosis and occlusion with a meta-analysis of prospective studies based on individual patient data. Methods: We searched Medline, Biosis Previews, Science Citation Index, The Cochrane Library, and EMBASE for studies in which patients with severe carotid artery stenosis or occlusion underwent Doppler CO2R testing (inhalation of CO2 or breath-holding) and were prospectively followed for ipsilateral ischemic stroke. Individual data from 754 patients from 9 studies were included. We used percentage cerebral blood flow velocity increase (pCi) during hypercapnia as the primary CO2R measure, and defined impaired reactivity as pCi <20% increase. Results: In a multiple regression model, impaired CO2R was independently associated with an increased risk of ipsilateral ischemic stroke (hazard ratio [HR] 3.69; confidence interval [CI] 2.01, 6.77; p < 0.0001). Risk prediction was similar for recently symptomatic vs asymptomatic patients. Using continuous values of pCi, a significant association between decreasing pCi and increasing risk of ipsilateral stroke was found: HR of 1.64 (95% CI 1.33, 2.02; p < 0.0001) per 10% decrease in pCi. For patients with asymptomatic internal carotid artery stenosis only (n = 330), a comparable stroke risk prediction was found: increasing HR 1.95 (95% CI 1.26, 3.04; p = 0.003) per 10% decrease in pCi. Conclusions: This analysis supports the usefulness of CO2R in risk prediction for patients with severe carotid artery stenosis or occlusion, both in recently symptomatic and asymptomatic patients. Further studies should evaluate whether treatment strategies in asymptomatic patients based on CO2R could improve patient outcomes.

Vascular predictors of cognitive decline in patients with mild cognitive impairment.

Our aim in this study was to assess the relationship between the state of cerebral vessels and the risk of conversion from mild cognitive impairment (MCI) to Alzheimers disease (AD). We included 117 MCI patients. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). After a 12-month follow-up period, neuropsychological examinations demonstrated a progression to dementia in 21 patients. Pathological values of BHI and IMT significantly increased the risk of conversion (BHI: odds ratio, 5.80; 95% confidence interval, 1.83-18.37, p < 0.05; IMT: odds ratio, 3.08; 95% confidence interval, 1.02-9.33; p < 0.05, multinomial logistic regression analysis). Comparison between patients with all normal values and those with the simultaneous alteration of the 2 vascular indexes showed an increase in the risk of conversion from 9% to 33% (ordinal regression analysis). Our findings show that alterations of cerebral vessel functional and anatomic status increase the risk of conversion from MCI to dementia.

Increased cerebral vasomotor reactivity in migraine with aura: an autoregulation disorder? A transcranial Doppler and near-infrared spectroscopy study

Migraine with aura (MA) is associated with changes in cerebral blood flow (CBF), whereas the role of cerebral autoregulation is uncertain. This study aimed to evaluate basal CBF, cerebral blood volume (CBV) and vasomotor reactivity (VMR) in MA patients. Twenty-one controls and 16 MA patients (eight with side predominance) underwent simultaneous examination of flow velocity in the middle cerebral arteries by transcranial Doppler (TCD) and of near-infrared spectroscopy (NIRS) parameters [oxygen haemoglobin saturation: oxygen%, and total haemoglobin content (THC)] at rest and after hypercapnia. Cerebral VMR, THC and oxygen% increases were significantly greater on the predominant compared with the non-predominant migraine side, with both sides of patients without side predominance and with controls. These findings suggest altered autoregulation in MA patients, possibly secondary to impaired cerebrovascular autonomic control. Simultaneous TCD and NIRS investigation could represent a non-invasive approach to evaluate cerebral haemodynamics at the cortical and subcortical level.

Severe carotid stenosis and impaired cerebral hemodynamics can influence cognitive deterioration

Objective: To evaluate whether severe carotid stenosis and related hemodynamics impairment may increase the risk of cognitive deterioration in asymptomatic subjects. Methods: A total of 210 subjects with unilateral asymptomatic severe carotid stenosis and 109 healthy controls were included and prospectively evaluated for a 36-month period. At entry, demographics, vascular risk profile, and pharmacologic treatments were defined. Cerebral hemodynamics was assessed by transcranial Doppler–based breath-holding index (BHI) test. Cognitive status was evaluated with the Mini-Mental State Examination (MMSE) at entry and at the end of the follow-up period. Cognitive deterioration was defined as a decrease in the MMSE score of 3 points or more during the overall follow-up period. Results: Subjects with carotid stenosis showed an increased probability of developing cognitive deterioration compared with the group without stenosis (odds ratio [OR] 4.16 [95% confidence interval (CI) 1.89–9.11]; p < 0.001). The presence of an impaired BHI ipsilateral to the stenosis was associated with an increased incidence of reduction in cognitive performance (OR 14.66 [95% CI 7.51–28.59]; p < 0.001). Conclusions: Our findings show that the presence of a severe carotid stenosis influences cognitive deterioration over a 36-month period in asymptomatic subjects. An associated hemodynamic impairment significantly increases the risk. Evaluation of functional consequences of carotid stenosis may offer the opportunity to select a group with an increased risk of developing cognitive impairment from subjects with asymptomatic severe carotid stenosis.

Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: A correlation study in patients with cognitive impairment

OBJECTIVE Intima-media thickness (IMT) seems associated with risk of Alzheimer disease (AD). Homocysteine (hcy) is a risk factor for vascular diseases and dementia. This study aimed at investigating the possible relationship among IMT, plasma hcy and C677T methylentetrahydrofolate reductase (MTHFR) polymorphism in relation to cognitive status. METHODS Sixty-three patients with cognitive impairment and 64 controls underwent biochemical, neuropsychological and carotid ultrasound assessment. RESULTS After age and folate adjustment, plasma hcy correlated with both Mini Mental State Examination (MMSE) score (r=-0.7, p<0.01) and IMT (r=0.7, p<0.01). Among patients with cognitive impairment, carriers of TT677 MTHFR genotype had plasma hcy (p<0.001) and IMT (p<0.01) values higher than non carriers. Furthermore, multiple regression analysis showed that MMSE scores were associated with plasma hcy (beta=-0.3, p=0.01), IMT (beta=-0.3, p=0.01) and TT677 MTHFR genotype (beta=-0.3, p=0.02). Structural equation modelling showed that the relation between hcy levels and MMSE score was partly direct (parameter estimate=-0.6; p=0.01) and partly mediated by IMT values (parameter estimate=-0.4; p=0.03). Finally, IMT resulted associated with hypertension (parameter estimate=0.8; p<0.0001). CONCLUSION Our findings suggest that TT677 MTHFR genotype promotes plasma homocysteine increase which in turn may favour intima-media thickening in patients with cognitive impairment. Hcy may promote neuronal damage through multiple mechanisms, including a micro-vascular damage, mediated by IMT increase, and a direct neuro-toxic effect.

Cortical Neuromodulation Modifies Cerebral Vasomotor Reactivity

Background and Purpose— Cerebral vasomotor reactivity (VMR) is a capability of cerebral vessels to dilate in response to hypercapnia. Transcranial direct current stimulation (tDCS) effects on cerebral hemodynamics have been poorly studied. Methods and Results— Ten healthy subjects underwent anodal/cathodal tDCS on the left motor cortex. Before and after tDCS, VMR assessment by transcranial Doppler and an electrocardiogram were performed. Normalized low-frequency band power of heart rate variability and its reactivity from basal to VMR condition (LFNreact) were estimated as relative markers of sympathetic activation. tDCS exerted a polarity-specific effect on both VMR (P=0.0001) and LFNreact (P=0.001). Anodal tDCS decreased VMR by 3.4%/mm Hg CO2 bilaterally and increased LFNreact, whereas cathodal tDCS increased VMR by 0.8%/mm Hg CO2 bilaterally and reduced LFNreact. Conclusions— Cerebral VMR is modified by tDCS. Based on the consensual changes with heart rate variability, we can hypothesize that the sympathetic nervous system could modulate the bihemispheric modification of VMR. Further studies are needed to confirm this hypothesis.

The longitudinal changes of BOLD response and cerebral hemodynamics from acute to subacute stroke. A fMRI and TCD study

BackgroundBy mapping the dynamics of brain reorganization, functional magnetic resonance imaging MRI (fMRI) has allowed for significant progress in understanding cerebral plasticity phenomena after a stroke. However, cerebro-vascular diseases can affect blood oxygen level dependent (BOLD) signal. Cerebral autoregulation is a primary function of cerebral hemodynamics, which allows to maintain a relatively constant blood flow despite changes in arterial blood pressure and perfusion pressure. Cerebral autoregulation is reported to become less effective in the early phases post-stroke.This study investigated whether any impairment of cerebral hemodynamics that occurs during the acute and the subacute phases of ischemic stroke is related to changes in BOLD response.We enrolled six aphasic patients affected by acute stroke. All patients underwent a Transcranial Doppler to assess cerebral autoregulation (Mx index) and fMRI to evaluate the amplitude and the peak latency (time to peak-TTP) of BOLD response in the acute (i.e., within four days of stroke occurrence) and the subacute (i.e., between five and twelve days after stroke onset) stroke phases.ResultsAs patients advanced from the acute to subacute stroke phase, the affected hemisphere presented a BOLD TTP increase (p = 0.04) and a deterioration of cerebral autoregulation (Mx index increase, p = 0.046). A similar but not significant trend was observed also in the unaffected hemisphere. When the two hemispheres were grouped together, BOLD TTP delay was significantly related to worsening cerebral autoregulation (Mx index increase) (Spearmans rho = 0.734; p = 0.01).ConclusionsThe hemodynamic response function subtending BOLD signal may present a delay in peak latency that arises as patients advance from the acute to the subacute stroke phase. This delay is related to the deterioration of cerebral hemodynamics. These findings suggest that remodeling the fMRI hemodynamic response function in the different phases of stroke may optimize the detection of BOLD signal changes.

Diffusion-weighted lesions after carotid artery stenting are associated with cognitive impairment.

The effect of carotid artery stenting (CAS) on cognitive function is still debated. Cerebral microembolism, detectable by post-procedural diffusion-weighted imaging (DWI) lesions, has been suggested to predispose to cognitive decline. Our study aimed at evaluating the effect of CAS on cognitive profile focusing on the potential role of cerebral microembolic lesions, taking into consideration the impact of factors potentially influencing cognitive status (demographic features, vascular risk profile, neuropsychological evaluation at baseline and magnetic resonance (MR) markers of brain structural damage). Thirty-seven patients with severe carotid artery stenosis were enrolled. Neurological assessment, neuropsychological evaluation and brain MR were performed the day before CAS (E0). Brain MR with DWI was repeated the day after CAS (E1), while neuropsychological evaluation was done after a 14-month median period (E2). Volumes of both white matter hyperintensities and whole brain were estimated at E0 on axial MR FLAIR and T1w-SE sequences, respectively. Unadjusted ANOVA analysis showed a significant CAS*DWI interaction for MMSE (F=7.154(32), p=.012). After adjusting for factors potentially influencing cognitive status CAS*DWI interaction was confirmed for MMSE (F=7.092(13), p=.020). Patients with DWI lesions showed a mean E2-E0 MMSE reduction of -3.1, while group without DWI lesions showed a mean E2-E0 MMSE of +1.1. Our study showed that peri-procedural brain microembolic load impacts negatively on cognitive functions, independently from the influence of patients-related variables.

What is the relationship among atherosclerosis markers, apolipoprotein E polymorphism and dementia?

Evidence suggests the important role of vascular factors both in vascular dementia (VaD) and Alzheimer disease (AD) pathogenesis. However, the relationship between apolipoprotein E (APOE) polymorphism and markers of atherosclerosis is still controversial. The aim of the study was to investigate the interplay between APOE polymorphisms and atherosclerosis in patients with AD and VaD. In this cross‐sectional study, 101 demented (68 AD and 33 VaD) patients underwent APOE genotyping and neck vessel ultrasound to evaluate carotid artery disease [intima‐media thickness (IMT) and plaques]. Patients with AD carrying ɛ4 allele presented increased IMT values with respect to non‐ɛ4 carriers and VaD patients, whereas no relation was found between APOE polymorphisms and the presence or grade of carotid plaques both in AD and VaD patients. The ɛ4 APOE allele may promote intima‐media thickening, interacting with other factors contributing to AD development.