Fabrizio Vernieri

Outcome of Carotid Artery Occlusion Is Predicted by Cerebrovascular Reactivity

BACKGROUND AND PURPOSE The purpose of this study was to investigate the possibility of obtaining prognostic indications in patients with internal carotid occlusion on the basis of intracranial hemodynamic status, presence of previous symptoms of cerebrovascular failure, and baseline characteristics. METHODS Cerebral hemodynamics were studied with transcranial Doppler ultrasonography. Cerebrovascular reactivity to apnea was calculated by means of the breath-holding index (BHI) in the middle cerebral arteries. Sixty-five patients with internal carotid artery occlusion were followed-up prospectively (median, 24 months), 23 patients were asymptomatic and 42 symptomatic (20 with transient ischemic attack and 22 with stroke). RESULTS During the follow-up period, 11 symptomatic patients and 1 asymptomatic patient had another ischemic event ipsilateral to carotid occlusion. Among factors considered, only lower BHI values in the middle cerebral arteries ipsilateral to carotid occlusion and older age were significantly associated with the risk of developing symptoms (P=0.002 and P=0.003, respectively; Cox regression multivariate analysis). Based on our data, a cut point of the BHI value for distinguishing between pathological and normal cerebrovascular reactivity was determined to be 0.69. All patients except one, who developed TIA or stroke during the follow-up period, had BHI values ipsilateral to carotid occlusion of <0.69. CONCLUSIONS These data suggest that impaired cerebrovascular reactivity is predictive for cerebral ischemic events in patients with carotid occlusion.

Elevation of serum copper levels in Alzheimer’s disease

Objective To determine whether serum trace metals and oxidative species are related to abnormal cognition in AD. Methods The authors studied serum peroxides, copper, iron, transferrin, and antioxidant capacity in 79 patients with AD (mean age 74.3 years; 25 men, 54 women) and in 76 cognitively normal individuals (mean age 70.1 years; 33 men, 43 women). The relation of these oxidative and trace metals to APOE &egr;4 allele frequency, neuropsychological performance, and cerebrovascular or atrophic burden, as estimated by brain MRI and ultrasonography of cerebral vessels, was evaluated. Results Copper level was higher (p < 0.001) in subjects with AD than control subjects (specificity = 95%, sensitivity = 60%) with a cutoff serum level of 16 &mgr;mol/L (1.02 mg/L). An increase of 1 &mgr;mol/L in serum copper accounted for 80% of the risk of having AD and correlated with poor neuropsychological performance and medial temporal lobe atrophy (p < 0.03). Antioxidant capacity decreased and correlated with medial temporal lobe atrophy (p < 0.009) and with APOE &egr;4 allele (p = 0.004). Conclusions Copper may play a role in neurodegenerative processes in AD, and serum copper measurement may prove to be a peripheral diagnostic marker for AD.

Effect of Collateral Blood Flow and Cerebral Vasomotor Reactivity on the Outcome of Carotid Artery Occlusion

Background and Purpose— Evidence suggests that an alteration in cerebral hemodynamics plays a relevant role in the occurrence of stroke in patients with carotid occlusion. The purpose of the present study was to evaluate the relationships among baseline characteristics, type and number of collateral pathways, cerebral vasomotor reactivity (VMR), and outcome of patients with carotid occlusion. Methods— One hundred four patients with symptomatic or asymptomatic internal carotid artery occlusion were followed up prospectively for a median period of 24 months. Cerebral VMR to apnea was calculated with transcranial Doppler ultrasonography by means of the breath-holding index (BHI) in the middle cerebral arteries. The patency of the 3 major intracranial collateral vessels was also evaluated. Results— During the follow-up period, 18 patients experienced an ischemic stroke ipsilateral to internal carotid artery occlusion. Among factors considered, only older age, number of collateral pathways, and BHI values in the middle cerebral artery ipsilateral to the occluded side were significantly associated with the risk of ipsilateral stroke (P <0.001, P =0.008, and P <0.001, respectively; multiple Cox regression analysis). A normal VMR and favorable prognosis characterized patients with full collateral development; in this group, no patient experienced an ischemic event. On the other hand, an impaired VMR and increased probability of experiencing a stroke were found in patients without collateral pathways; the annual risk of ipsilateral stroke in this group was 32.7%. Patients with 1 or 2 collateral pathways showed a different VMR ranging from normal to strongly reduced BHI values. The ipsilateral stroke event risk was 17.5% in patients with 1 collateral vessel and 2.7% in patients with 2 collateral pathways. In this case, the risk of cerebrovascular events occurring during the follow-up period was significantly related to VMR. Conclusions— These data suggest that cerebral hemodynamic status in patients with carotid occlusive disease is influenced by both individual anatomic and functional characteristics. The planning of strategies to define the risk profile and any attempt to influence patients’ outcome should be based on the evaluation of the intracranial hemodynamic adaptive status, with particular attention to the number of collateral vessels and the related VMR.

Cerebrovascular Reactivity and Cognitive Decline in Patients With Alzheimer Disease

Background and Purpose— The aim of this study was to explore the possible contribution of alterations in cerebral hemodynamics to the evolution of cognitive impairment in patients with Alzheimer disease (AD). Method— Fifty-three patients with AD were investigated. The evolution of cognitive decline over 12 months was evaluated by means of changes in Mini Mental State Examination (MMSE) and AD Assessment Scale for Cognition (ADAS-Cog) scores. Demographic characteristics, vascular risk profile, pharmacological treatment, and presence of white matter lesions were assessed at entry. Further, a basal evaluation of cerebrovascular reactivity to hypercapnia was measured with transcranial Doppler ultrasonography using the breath-holding index (BHI). Results— Of all the variables considered, both MMSE and ADAS-Cog changes had the highest correlation with BHI, followed by age and diabetes. After subdividing both cognitive measures reductions into bigger and smaller-than-average decline (2 points for MMSE; 5 points for ADAS-Cog), multiple logistic regression indicated BHI as the sole significant predictor of cognitive decline. Conclusions— These results show an association between impaired cerebral microvessels functionality and unfavorable evolution of cognitive function in patients with AD. Further research is needed to fully establish whether altered cerebral hemodynamics may be considered an independent factor in sustaining cognitive decline progression or an effect of pathological processes involved in AD.

Excess of serum copper not related to ceruloplasmin in Alzheimer disease

Objective: To assess the role of serum copper in relation to ceruloplasmin and other peripheral markers of inflammation in Alzheimer disease (AD). Methods: The authors studied serum levels of copper, ceruloplasmin, and transferrin, as well as total peroxides, antioxidants, and other peripheral markers of inflammation in 47 patients with AD, 24 patients with vascular dementia (VaD), and 44 healthy controls. Biochemical variables were related to the patients’ and controls’ clinical status. Results: The authors found that copper (p < 0.001), peroxides (p = 0.026), and ceruloplasmin (p = 0.052) were increased and TRAP was decreased (p = 0.006) in patients with AD, while no other markers of inflammation were altered. The calculation of the ratio between copper and ceruloplasmin suggested the presence in the serum of AD patients, but not of VaD or normal controls, of a large pool of non-ceruloplasmin-bound copper. Conclusions: Changes in the distribution of the serum copper components, consisting of an increase of a copper fraction not explained by ceruloplasmin, seem to be characteristic of Alzheimer disease and may be implicated in the pathogenesis of the disease.

Longitudinal prognostic value of serum “free” copper in patients with Alzheimer disease

Background: Serum copper not bound to ceruloplasmin (“free”) appears slightly elevated in patients with Alzheimer disease (AD). We explored whether a deregulation of the free copper pool can predict AD clinical worsening. Methods: We assessed levels of copper, iron, zinc, transferrin, ceruloplasmin, peroxides, total antioxidant capacity, free copper, and apolipoprotein E genotype in 81 patients with mild or moderate AD, mean age 74.4, SD = 7.4 years, clinically followed up after 1 year. The association among biologic variables under study and Mini-Mental State Examination (MMSE) (primary outcome), activities of daily living (ADL), and instrumental activities of daily living (IADL) (secondary outcomes) performed at study entry and after 1 year were analyzed by multiple regression. Results: Free copper predicted the annual change in MMSE, adjusted for the baseline MMSE by means of a linear regression model: it raised the explained variance from 2.4% (with only sex, age, and education) to 8.5% (p = 0.026). When the annual change in MMSE was divided into <3 or ≥3 points, free copper was the only predictor of a more severe decline (predicted probability of MMSE worsening 23%: odds ratio = 1.23; 95% confidence interval = 1.03–1.47; p = 0.022). Hyperlipidemic patients with higher levels of free copper seemed more prone to worse cognitive impairment. Free copper at baseline correlated with the ADL and IADL clinical scales scores at 1 year. Conclusions: These results show an association between copper deregulation and unfavorable evolution of cognitive function in Alzheimer disease. Further research is needed to establish whether copper is an independent risk factor for cognitive decline.

Resting EEG sources correlate with attentional span in mild cognitive impairment and Alzheimer's disease

Previous evidence has shown that resting delta and alpha electroencephalographic (EEG) rhythms are abnormal in patients with Alzheimers disease (AD) and its potential preclinical stage (mild cognitive impairment, MCI). Here, we tested the hypothesis that these EEG rhythms are correlated with memory and attention in the continuum across MCI and AD. Resting eyes‐closed EEG data were recorded in 34 MCI and 53 AD subjects. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). EEG cortical sources were estimated by low‐resolution brain electromagnetic tomography (LORETA). These sources were correlated with neuropsychological measures such as Rey list immediate recall (word short‐term memory), Rey list delayed recall (word medium‐term memory), Digit span forward (immediate memory for digits probing focused attention), and Corsi span forward (visuo‐spatial immediate memory probing focused attention). A statistically significant negative correlation (Bonferroni corrected, P < 0.05) was observed between Corsi span forward score and amplitude of occipital or temporal delta sources across MCI and AD subjects. Furthermore, a positive correlation was shown between Digit span forward score and occipital alpha 1 sources (Bonferroni corrected, P < 0.05). These results suggest that cortical sources of resting delta and alpha rhythms correlate with neuropsychological measures of immediate memory based on focused attention in the continuum of MCI and AD subjects.

Resting state cortical electroencephalographic rhythms are related to gray matter volume in subjects with mild cognitive impairment and Alzheimer's disease

Cortical gray matter volume and resting state cortical electroencephalographic rhythms are typically abnormal in subjects with amnesic mild cognitive impairment (MCI) and Alzheimers disease (AD). Here we tested the hypothesis that in amnesic MCI and AD subjects, abnormalities of EEG rhythms are a functional reflection of cortical atrophy across the disease. Eyes‐closed resting state EEG data were recorded in 57 healthy elderly (Nold), 102 amnesic MCI, and 108 AD patients. Cortical gray matter volume was indexed by magnetic resonance imaging recorded in the MCI and AD subjects according to Alzheimers disease neuroimaging initiative project (http://www.adni‐info.org/). EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10.5 Hz), alpha2 (10.5–13 Hz), beta1 (13–20 Hz), beta2 (20–30 Hz), and gamma (30–40 Hz). These rhythms were indexed by LORETA. Compared with the Nold, the MCI showed a decrease in amplitude of alpha 1 sources. With respect to the Nold and MCI, the AD showed an amplitude increase of delta sources, along with a strong amplitude reduction of alpha 1 sources. In the MCI and AD subjects as a whole group, the lower the cortical gray matter volume, the higher the delta sources, the lower the alpha 1 sources. The better the score to cognitive tests the higher the gray matter volume, the lower the pathological delta sources, and the higher the alpha sources. These results suggest that in amnesic MCI and AD subjects, abnormalities of resting state cortical EEG rhythms are not epiphenomena but are strictly related to neurodegeneration (atrophy of cortical gray matter) and cognition. Hum Brain Mapp, 2013.

Cerebral hemodynamics and cognitive performance in patients with asymptomatic carotid stenosis

Objective: The aim of this study was to investigate whether the presence of severe internal carotid artery stenosis may be associated with different cognitive performance in relation to the side of the stenosis and its hemodynamic consequences. Methods: Eighty-three patients with asymptomatic severe unilateral internal carotid stenosis were included. A neuropsychological investigation including Verbal Fluency using phonemic and category access, Coloured Progressive Matrices, and Complex Figure Test Copy was performed. Each patient underwent an assessment of cerebrovascular reactivity (CVR) to hypercapnia with transcranial Doppler ultrasonography using the breath-holding index (BHI). Thirty healthy subjects comparable for demographic characteristics and vascular risk profile served as controls. Subjects with carotid stenosis were classified into two groups: preserved CVR (BHI ≥0.69), 48 patients (25 with left and 23 with right stenosis); and impaired CVR (BHI <0.69), 35 patients (19 with left and 16 with right stenosis). Results: Subjects with left stenosis and reduced CVR had significantly lower performances at phonemic verbal fluency with respect to controls and the other groups of stenosis. In subjects with right stenosis and reduced CVR, scores obtained in Coloured Progressive Matrices and in Complex Figure Test Copy were significantly lower with respect to the other groups. Conclusions: These results suggest that an alteration of cerebrovascular reactivity may be responsible for reduction in some cognitive abilities involving the function of the hemisphere ipsilateral to carotid stenosis. Such findings may be of interest for providing a more comprehensive indication to surgical treatment in subgroups of subjects with asymptomatic carotid stenosis.

Transcranial Doppler and Near-Infrared Spectroscopy Can Evaluate the Hemodynamic Effect of Carotid Artery Occlusion

Background and Purpose— Cerebral hemodynamic and metabolic changes can compensate for the decrease in cerebral blood flow occurring in patients with carotid occlusive disease. At present, a complete assessment of the cerebral adaptive status is only possible with positron-emission tomography. Near-infrared spectroscopy (NIRS) is a noninvasive technique that, providing a real time assessment of fluctuations in cerebral hemoglobin, has been used to estimate the cerebral blood volume and to measure cerebral vasomotor reactivity (VMR). Moreover, NIRS technology, by allowing the absolute measurement of absorption and scattering coefficients of brain, can determine the oxyhemoglobin and deoxyhemoglobin concentrations in situ in the blood stream. Methods— In order to evaluate different aspects of the cerebral hemodynamic status, 27 subjects with symptomatic and asymptomatic carotid artery occlusion and 30 healthy subjects underwent a simultaneous examination by means of transcranial Doppler (TCD), able to reliably detect collateral circulation and VMR, and NIRS at rest condition and during CO2 reactivity test. Results— The main finding of this study was the demonstration of a difference between asymptomatic and symptomatic patients in terms of mean flow velocity increase (52.4% versus 21.0%; P <0.001) estimated by TCD and of hemoglobin saturation increase measured by NIRS (6.8% versus 3.8%; P =0.015). Conclusions— The opportunity to perform NIRS and TCD simultaneously provides useful information about both hemodynamic and metabolic cerebral adaptive status in patients with occlusive disease in a simple, noninvasive, and reliable way.