José L. Zubieta

Neuroimaging as a marker of the onset and progression of Alzheimer's disease

Several neuroimaging techniques are promising tools as early markers of brain pathology in Alzheimers disease (AD). On structural MRI, atrophy of the entorhinal cortex is present already in mild cognitive impairment (MCI). In the autosomal dominant forms of AD, the rate of atrophy of medial temporal structures separates affected from control persons even 3 years before the clinical onset of cognitive impairment. The elevated annual rate of brain atrophy offers a surrogate tool for the evaluation of newer therapies using smaller samples, thereby saving time and resources. On functional MRI, activation paradigms activate a larger area of parieto-temporal association cortex in persons at higher risk for AD, whereas the entorhinal cortex activation is lesser in MCI. Similar findings have been detected with activation procedures and water (H(2)(15)O) PET. Regional metabolism in the entorhinal cortex, studied with FDG PET, seems to predict normal elderly who will deteriorate to MCI or AD. SPECT shows decreased regional perfusion in limbic areas, both in MCI and AD, but with a lower likelihood ratio than PET. Newer PET compounds allow for the determination in AD of microglial activation, regional deposition of amyloid and the evaluation of enzymatic activity in the brain of AD patients.

Quantitative volumetric analysis of gliomas with sequential MRI and 11C-methionine PET assessment: patterns of integration in therapy planning

PurposeThe aim of the study was to evaluate the volumetric integration patterns of standard MRI and 11C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade.MethodsWe studied 23 patients with suspected or previously treated glioma who underwent preoperative 11C-methionine PET because MRI was imprecise in defining the surgical target contour. Images were transferred to the treatment planning system, coregistered and fused (BrainLAB). Tumour delineation was performed by 11C-methionine PET thresholding (vPET) and manual segmentation over MRI (vMRI). A 3-D volumetric study was conducted to evaluate the contribution of each modality to tumour target volume. All cases were surgically treated and histological classification was performed according to WHO grades. Additionally, several biopsy samples were taken according to the results derived either from PET or from MRI and analysed separately.ResultsFifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high 11C-methionine uptake without correspondence in MRI showed tumour proliferation, including infiltrative zones, distinguishing them from dysplasia and radionecrosis. Two main PET/MRI integration patterns emerged after analysis of volumetric data: pattern vMRI-in-vPET (11/23) and pattern vPET-in-vMRI (9/23). Besides, a possible third pattern with differences in both directions (vMRI-diff-vPET) could also be observed (3/23). There was a statistically significant association between the tumour classification and integration patterns described above (p < 0.001, κ = 0.72). GBM was associated with pattern vMRI-in-vPET (9/10), low-grade with pattern vPET-in-vMRI (7/8) and anaplastic with pattern vMRI-diff-vPET (3/5).ConclusionThe metabolically active tumour volume observed in 11C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in 11C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas.

Grey matter hypometabolism and atrophy in Parkinson’s disease with cognitive impairment: a two-step process

The pathophysiological process underlying cognitive decline in Parkinsons disease is not well understood. Cerebral atrophy and hypometabolism have been described in patients with Parkinsons disease and dementia or mild cognitive impairment with respect to control subjects. However, the exact relationships between atrophy and hypometabolism are still unclear. To determine the extension and topographical distribution of hypometabolism and atrophy in the different cognitive states of Parkinsons disease, we examined 46 patients with Parkinsons disease (19 female, 27 male; 71.7 ± 5.9 years old; 14.6 ± 4.2 years of disease evolution; modified Hoehn and Yahr mean stage 3.1 ± 0.7). Cognitive status was diagnosed as normal in 14 patients, as mild cognitive impairment in 17 and as dementia in 15 patients. Nineteen normal subjects (eight female, 11 male; 68.1 ± 3.2 years old) were included as controls. (18)F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging scans were obtained, co-registered, corrected for partial volume effect and spatially normalized to the Montreal Neurological Institute space in each subject. Smoothing was applied to the positron emission tomography and magnetic resonance imaging scans to equalize their effective smoothness and resolution (10 mm and 12 mm full-width at half-maximum and Gaussian kernel, respectively). Z-score maps for atrophy and for hypometabolism were obtained by comparing individual images to the data set of control subjects. For each group of patients, a paired Students t-test was performed to statistically compare the two Z-map modalities (P < 0.05 false discovery rate corrected) using the direct voxel-based comparison technique. In patients with mild cognitive impairment, hypometabolism exceeded atrophy in the angular gyrus, occipital, orbital and anterior frontal lobes. In patients with dementia, the hypometabolic areas observed in the group with mild cognitive impairment were replaced by areas of atrophy, which were surrounded by extensive zones of hypometabolism. Areas where atrophy was more extended than hypometabolism were found in the precentral and supplementary motor areas in both patients with mild cognitive impairment and with dementia, and in the hippocampus and temporal lobe in patients with dementia. These findings suggest that there is a gradient of severity in cortical changes associated with the development of cognitive impairment in Parkinsons disease in which hypometabolism and atrophy represent consecutive stages of the same process in most of the cortical regions affected.

Preoperative planning of DIEP and SGAP flaps: preliminary experience with magnetic resonance angiography using 3-tesla equipment and blood-pool contrast medium.

BACKGROUND Autologous breast reconstruction techniques can be used to create a breast, in particular the superior gluteal artery perforator (SGAP) and deep inferior epigastric artery perforator (DIEP) flaps. Preoperative imaging is an essential planning tool in mapping the location and size of perforator vessels. The aim of this report is to show the usefulness of angio-MR technique for preoperative planning of DIEP and SGAP flaps. Initial experience, surgical findings correlation and imaging findings will be described. METHODS From February 2007 to September 2007, ten consecutive women considered for breast reconstruction with DIEP (eight patients) and SGAP flaps (two patients) after previous mastectomy for breast cancer were studied. After written informed consent was obtained, a preoperative angio-MR using 3-Tesla equipment and blood-pool contrast medium was performed to localize and evaluate the main perforator vessels in each patient and procedure. RESULTS Angio-MR showed all the main perforator vessels later observed during the surgical procedure with a very good location concordance, but missed one main perforator vessels in each of two patients. In all patients undergoing SGAP flaps, an accurate identification of the main perforator vessels was achieved. Angio-MR clearly showed the intramuscular course of the perforator vessels for DIEP and SGAP flaps. Exact correlation between angio-MR and surgical findings was observed. CONCLUSIONS The use of angio-MR for preoperative perforator flaps evaluation yielded promising results and would allow not only to locate perforator vessels but also to globally assess presurgical planning of perforator flaps in a noninvasive, radiation and toxicity-free way.

Independent Association of Fibrinogen with Carotid Intima-Media Thickness in Asymptomatic Subjects

Background: Fibrinogen has been found to be an independent risk factor for cardiovascular disease. Both genetic and environmental factors contribute to its variability in plasma. However, whether the relation between fibrinogen and carotid intima-media thickness (IMT) is independent of those factors has not been established. Therefore, the aim of this study was to investigate the relations of plasma fibrinogens and the –455 G/A Bβ-fibrinogen polymorphism with the carotid IMT in a series of asymptomatic subjects. Methods: Markers of inflammation, C-reactive protein (CRP) and leukocytes, and endothelial perturbation (von Willebrand factor, vWF) were measured in 135 subjects. All individuals underwent a complete clinical examination and lipid measurements (cholesterol and its fractions HDL and LDL and triglycerides). The carotid IMT was measured by B-mode ultrasound in the common carotid artery. Results: Patients in the highest fibrinogen tertile had a significantly higher BMI (p < 0.01), LDL-cholesterol (p < 0.01), leukocyte count, CRP and vWF (p < 0.001). In the univariate model a strong positive relationship was found between plasma fibrinogen and carotid IMT (p < 0.01). Fibrinogen also correlated positively with age, BMI, arterial systolic pressure, cholesterol, cholesterol-LDL, smoking, CRP and vWF (p < 0.01). In the multivariate analysis, the association of fibrinogen with carotid IMT remained significant (p < 0.01) after adjustment for all the parameters analyzed. Conclusion: In a population sample of adults without clinically overt atherosclerotic disease, elevated fibrinogen was related to carotid IMT independent of a wide range of important confounding variables.

Benign Paroxysmal Positional Vertigo in Patients With Ménière's Disease Treated With Intratympanic Gentamycin

Objectives To analyze the incidence and characteristics of benign paroxysmal positional vertigo (BPPV) in patients with Ménières disease who did not respond to medical treatment and to whom intratympanic gentamycin treatment was proposed.

Neuronal activity of the red nucleus in Parkinson's disease

Precise placement of the electrodes for stimulation of the subthalamic nucleus (STN) in Parkinsons disease (PD) is crucial for the therapeutic benefit. As a result of the mistargeting and misplacement of the electrodes during surgery in 2 patients with PD, we have characterized the neuronal firing in the red nucleus (RN) and observed the effects of stimulation of this nucleus. Although the neuronal firing (mean ± SD) of the RN (34 ± 4.4 Hz) resembles that described for the STN (33.1 ± 16.6 Hz), a higher proportion of cells responded to the movement of the contralateral limbs (70–80%). Stimulation in the area of the RN‐induced intolerable side effects without motor improvement. We conclude that the STN and RN have some similar neurophysiological features but can be distinguished intraoperatively. This initial description of the physiological characteristics of the RN in humans will draw attention to the possibility of confusing the RN and STN during intraoperative recording.

New MRI, 18F-DOPA and 11C-(+)-α-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: Advantages to improve PET quantification

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of (18)F-DOPA and (11)C-(+)-alpha-dihydrotetrabenazine ((11)C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinsons disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, (18)F-DOPA and (11)C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of (11)C-DTBZ PET. A symmetric reduction in striatal (11)C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet.

Reduced Cerebral Blood Flow in Mild Cognitive Impairment Assessed Using Phase-Contrast MRI

There is increasing evidence of a vascular contribution to Alzheimers disease (AD). In some cases, prior work suggests that chronic brain hypoperfusion could play a prime pathogenic role contributing to the accumulation of amyloid-β,while other studies favor the hypothesis that vascular dysfunction and amyloid pathology are independent, although synergistic, mechanisms contributing to cognitive impairment. Vascular dysfunction can be evaluated by assessing cerebral blood flow impairment. Phase contrast velocity mapping by MRI offers a non-invasive means of quantifying the total inflow of blood to the brain. This quantitative parameter could be a sensitive indicator of vascular disease at early stages of AD. In this work, phase contrast MRI was used to evaluate cerebral hemodynamics in patients with subjective memory complaints, amnestic mild cognitive impairment, and mild to moderate AD, and compare them with control subjects. Results showed that blood flow and velocity were decreased in the patients with cognitive dysfunction and the decrease correlated with the degree of cognitive impairment as assessed by means of neuropsychological tests. Total cerebral blood flow measurements were clearly reduced in AD patients, but more importantly appeared to be sensitive enough to distinguish between healthy subjects and those with mild cognitive impairment. A quantitative measurement of total brain blood flow could potentially predict vascular dysfunction and compromised brain perfusion in early stages of AD.

Atraumaticity study of 2 cochlear implant electrode arrays.

Hypothesis Evaluate, based on morphologic and histologic parameters, the atraumaticity of 2 electrode arrays implanted in 10 human temporal bones. Background Atraumatic surgery and electrode arrays are current topics in otologic surgery. The preservation of cochlear anatomy and its functions is a priority and morphologic evaluation of the surgical trauma is essential to continue improving in this field. Methods Ten preserved human temporal bones (TB) without anatomic alterations were used in this study. They were divided into 2 groups of 5, and atraumatic surgery was performed to insert HiFocus 1J (group A) and HiFocus Helix (group B) electrode arrays. Anatomic comparisons were performed using computed tomography and histologic analysis. Results Group A: the mean length for the cochlear longitudinal axis was 10.30 mm, and the cochlear transversal axis was 7.2 mm. Scala tympani insertion was achieved in 4/5 TB studied, with a mean depth and angle of insertion of 19.2 mm and 325.5°, respectively. Lateral location of the electrode array was achieved in all specimens. No significant correlation was observed between these dimensions and depth of insertion. Group B: the mean length for the cochlear longitudinal axis was 9.52 mm, and cochlear transversal axis was 6.38 mm. Scala tympani insertion was achieved in 4/5 TB studied, with a mean depth and angle of insertion of 17.5 mm and 352°, respectively. Modiolar location of the electrode array was achieved in all specimens. A positive correlation was established between the linear and angular insertion depths (p = 0.044). Conclusion In summary, it is safe to state that neither electrode array shows significant insertion trauma.