The relationship between neurophysiological and cerebrovascular–metabolic findings in patients affected by severe cerebrovascular deficits was investigated by comparing magnetoencephalographic (MEG‐evoked fields) and blood oxygen level‐dependent functional MRI (BOLD fMRI) responses to median nerve electric stimulation. Despite the use of identical stimuli, the two techniques elicited always‐detectable responses in the control group (10 subjects), but demonstrated uncorrelated activation properties in our patient sample (10 subjects). All patients showed clear MEG signals in both the affected and unaffected hemispheres, indicating well synchronized, stimulus‐locked firing of neurons in the primary sensorimotor cortex, but some patients showed no fMRI activation in either the affected or the unaffected hemisphere. In order to clarify the origin of this uncoupling, we investigated the possible role of lesion site, white matter hyperintensities, current medication, risk factors, anatomy of the neck vessels, and cerebral vasomotor reactivity (VMR) as measured by transcranial Doppler (TCD) during CO₂ inhalation. Neither neuronal activation properties nor any of the considered factors were related to the lack of fMRI activation, with the exception of altered vasomotor reactivity, which was, on the contrary, strongly related. Preserved VMR was paired with absent BOLD bilaterally in the only patient affected by microangiopathy. This finding suggests that BOLD contrast could be more sensitive than TCD to chronic microvascular impairments, measuring small‐ rather than large‐ vessel reactivity.

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.

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.

Paolucci M, et al. J Clin Neurol. 2021 Apr;17(2):164-175. https://doi.org/10.3988/jcn.2021.17.2.164

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.