Francesca B. Pizzini

Mapping local hippocampal changes in Alzheimer's disease and normal ageing with MRI at 3 Tesla

Histological studies have suggested differing involvement of the hippocampal subfields in ageing and in Alzheimers disease. The aim of this study was to assess in vivo local hippocampal changes in ageing and Alzheimers disease based on high resolution MRI at 3 Tesla. T(1)-weighted images were acquired from 19 Alzheimers disease patients [age 76 +/- 6 years, three males, Mini-Mental State Examination 13 +/- 4] and 19 controls (age 74 +/- 5 years, 11 males, Mini-Mental State Examination 29 +/- 1). The hippocampal formation was isolated by manual tracing. Radial atrophy mapping was used to assess group differences and correlations by averaging hippocampal shapes across subjects using 3D parametric surface mesh models. Percentage difference, Pearsons r, and significance maps were produced. Hippocampal volumes were inversely correlated with age in older healthy controls (r = 0.56 and 0.6 to the right and left, respectively, P < 0.05, corresponding to 14% lower volume for every 10 years of older age from ages 65 to 85 years). Ageing-associated atrophy mapped to medial and lateral areas of the tail and body corresponding to the CA1 subfield and ventral areas of the head corresponding to the presubiculum. Significantly increased volume with older age mapped to a few small spots mainly located to the CA1 sector of the right hippocampus. Volumes were 35% and 30% smaller in Alzheimers disease patients to the right and left (P < 0.0005). Alzheimers disease-associated atrophy mapped not only to CA1 areas of the body and tail corresponding to those also associated with age, but also to dorsal CA1 areas of the head unaffected by age. Regions corresponding to the CA2-3 fields were relatively spared in both ageing and Alzheimers disease. Hippocampal atrophy in Alzheimers disease maps to areas in the body and tail that partly overlap those affected by normal ageing. Specific areas in the anterior and dorsal CA1 subfield involved in Alzheimers disease were not in normal ageing. These patterns might relate to differential neural systems involved in Alzheimers disease and ageing.

Microstructural diffusion changes are independent of macrostructural volume loss in moderate to severe Alzheimer's disease.

Although it is established that Alzheimers disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD. Seventeen patients with moderate-severe AD and 13 healthy volunteers underwent diffusion-weighted and T1-weighted MR scanning. Images were processed to obtain measures of macrostructural atrophy (gray and white matter volumes) and microstructural damage (fractional anisotropy and mean diffusivity). Microstructural diffusion changes independent of macrostructural loss were investigated using an ANCOVA where macrostructural maps were used as voxel-wise covariates. The reverse ANCOVA model was also assessed, where macrostructural loss was the dependent variable and microstructural diffusion tensor imaging maps were the imaging covariates. Diffusion differences between patients and controls were observed after controlling for volumetric differences in medial temporal, retrosplenial regions, anterior commissure, corona radiata, internal capsule, thalamus, corticopontine tracts, cerebral peduncle, striatum, and precentral gyrus. Independent volumetric differences were observed in the entorhinal cortex, inferior temporal lobe, posterior cingulate cortex, splenium and cerebellum. While it is well known that AD is associated with pronounced volumetric change, this study suggests that measures of microstructure provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD and in those thought to be spared. As such this work provides great understanding of the topography of pathological changes in AD that can be captured with imaging.

Effect of memantine on resting state default mode network activity in Alzheimer's disease.

BackgroundMemantine is an approved symptomatic treatment for moderate to severe Alzheimer’s disease that reduces the excitotoxic effects of hyperactive glutamatergic transmission. However, the exact mechanism of the effect of memantine in Alzheimer’s disease patients is poorly understood. Importantly, the default mode network (DMN), which plays a key role in attention, is hypoactive in Alzheimer’s disease and is under glutamatergic control.ObjectiveTo assess the effect of memantine on the activity of the DMN in moderate to severe Alzheimer’s disease.MethodsFunctional magnetic resonance imaging (MRI) data from 15 patients with moderate to severe Alzheimer’s disease, seven treated with memantine (mean±SD age 77±8 years, mean±SD Mini-Mental State Examination [MMSE] score 16±5) and eight with placebo (mean±SD age 76±6 years, mean±SD MMSE score 13±1), were acquired at baseline (T0) and after 6 months of treatment (T6). Resting state components were extracted after spatial normalization in individual patients with independent component analysis. The consistency of the components was assessed using ICASSO and the DMN was recognized through spatial correlation with a pre-defined template. Voxel-based statistical analyses were performed to study the change in DMN activity from T0 to T6 in the two groups.ResultsAt T0, the two groups showed similar DMN activity except in the precuneus and cuneus, where the patients who started treatment with memantine had slightly greater activity (p <0.05 corrected for familywise error [FWE]). The prospective comparison between T0 and T6 in the treated patients showed increased DMN activation mapping in the precuneus (p <0.05, FWE corrected), while the prospective comparison in the untreated patients did not show significant changes. The treatment×time interaction term was significant at p <0.05, FWE corrected.ConclusionsThe results suggest a positive effect of memantine treatment in patients with moderate to severe Alzheimer’s disease, resulting in an increased resting DMN activity in the precuneus region over 6 months. Future studies confirming the present findings are required to further demonstrate the beneficial effects of memantine on the DMN in Alzheimer’s disease.

A dehiscent superior semicircular canal may be plugged and resurfaced via the transmastoid route.

Objective: To evaluate the results obtained in treating superior semicircular canal dehiscence by plugging and resurfacing the defect via the transmastoid approach. Patients: Six patients (30-70 yr old) who had disabling semicircular canal dehiscence syndrome underwent surgery. Intervention: After a wide mastoidectomy and skeletonization of the semicircular canals, a shell of bone covering the middle fossa lateral to the superior semicircular canal was removed. The exposed dura was gently retracted and the canal skeletonized. Bone dust mixed with fibrine glue and bone wax were pressed to plug the dehiscent portion of the canal, and a slice of cortical bone was inserted to resurface it. Main Outcome Measure: Recovery from vestibular and auditory symptoms was evaluated. Results: No intraoperative or postoperative complications occurred. Patients experienced an immediate relief of symptoms attributable to the dehiscence. Conclusion: A superior semicircular canal dehiscence may be plugged and resurfaced via the transmastoid approach, thus avoiding the more invasive middle fossa craniotomy.

Reliability of magnetic resonance imaging performed after intratympanic administration of gadolinium in the identification of endolymphatic hydrops in patients with Ménière's disease.

Objective: To evaluate the reliability of magnetic resonance imaging performed after intratympanic gadolinium administration in evidencing endolymphatic hydrops in patients with Ménières disease (MD). Patients: A total of 26 patients (18 male and 8 female subjects, aged 25-78 yr; median age, 56 yr) with definite MD and 12 subjects (8 male and 4 female subjects, aged 31-75 yr; median age, 51 yr) with various unilateral non-MD disorders of the inner ear were examined. Intervention: A 0.6-ml solution of gadobutrol (1 mmol/ml), diluted 1:7 in saline, was injected in the affected ear through the inferior-posterior quadrant of the tympanic membrane, using a 22-gauge spinal needle. In 9 MD patients, the contralateral ear also was injected. The patient was kept with the head rotated 45 degrees contralaterally for 30 minutes after each injection. Twenty-four hours later, a 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging using a 3 Tesla unit was performed. Main Outcome Measure: Perilymphatic enhancement was evaluated in different portions of the labyrinth in MD ears and compared with the outcomes obtained in the non-MD ears. Results: All MD ears showed impaired perilymphatic enhancement of variable degrees. No enhancement defects could be observed in all examined contralateral unaffected ear of the patients with MD, as well as in 11 of the 12 ears of the subjects with various unilateral non-MD disorders. Conclusion: Perilymphatic enhancement defect of variable degrees is observed in the pathologic ear of every patient with MD. The consistency of this phenomenon in MD ears and the complete enhancement in most of the ears without MD safely enable to attribute these findings to endolymphatic hydrops. It is likely in the near future that imaging may be used to achieve a certain diagnosis of MD in life.

HASTE diffusion-weighted 3-Tesla magnetic resonance imaging in the diagnosis of primary and relapsing cholesteatoma.

Objective: To evaluate the value of half-Fourier acquisition single-shot turbo-spin-echo diffusion-weighted magnetic resonance imaging (HASTE DW MRI) using a 3-Tesla (3T) unit in the diagnosis of primary and relapsing cholesteatoma. Study Design: Retrospective observational investigation. Setting: Tertiary referral center. Patients: Seventeen patients suspected of having a primary cholesteatoma without clear clinical evidence of the lesion, and 13 patients who were candidates to a second-stage tympanoplasty to rule out a relapsing cholesteatoma or reconstruct the ossicular chain were investigated. Intervention: All patients were scanned in a 3T scanner with a 4-channel head coil using T2 HASTE DW MRI technique sequences in axial and coronal planes covering the middle ear and mastoid regions. Main Outcome Measure: Images were considered positive for cholesteatoma in the presence of a hyperintense, patchy-like lesion in the petrous bone. Results: Images showed a high signal intensity suggestive of primary cholesteatoma in 10 of 17 patients and of relapsing cholesteatoma in 7 of 13 patients. Of the 17 subjects, 15 with positive MRI findings were operated on, and the presence of cholesteatoma (ranging from 2 to 20 mm in size) was confirmed at surgery. Of the 13 subjects shown to be negative on HASTE DW MRI for cholesteatoma, 11 were operated on and were all confirmed to be cholesteatoma-free. Conclusion: Half-Fourier acquisition single-shot turbo-spin-echo diffusion-weighted magnetic resonance imaging technique, using a 3T unit, may be a diagnostic tool for a rapid and highly reliable discrimination between cholesteatomatous and noncholesteatomatous tissue in the middle ear, with 100% of positive and negative predictive values.

Combining ESI, ASL and PET for quantitative assessment of drug-resistant focal epilepsy

When localization of the epileptic focus is uncertain, the epileptic activity generator may be more accurately identified with non-invasive imaging techniques which could also serve to guide stereo-electroencephalography (sEEG) electrode implantation. The aim of this study was to assess the diagnostic value of perfusion magnetic resonance imaging with arterial spin labeling (ASL) in the identification of the epileptogenic zone, as compared to the more invasive positron-emission tomography (PET) and other established investigation methods for source imaging of electroencephalography (EEG) data. In 6 patients with drug-resistant focal epilepsy, standard video-EEG was performed to identify clinical seizure semeiology, and high-density EEG, ASL and FDG-PET to non-invasively localize the epileptic focus. A standardized source imaging procedure, low-resolution brain electromagnetic tomography constrained to the individual matter, was applied to the averaged spikes of high-density EEG. Quantification of current density, cerebral blood flow, and standardized uptake value were compared over the same anatomical areas. In most of the patients, source in the interictal phase was associated with an area of hypoperfusion and hypometabolism. Conversely, in the patients presenting with early post-ictal discharges, the brain area identified by electrical source imaging (ESI) as the generating zone appeared to be hyperperfused. In 2 patients in whom the focus remained uncertain, the postoperative follow-up showed the disappearance of epileptic activity. As an innovative and more comprehensive approach to the study of epilepsy, the combined use of ESI, perfusion MRI, and PET may play an increasingly important role in the non-invasive evaluation of patients with refractory focal epilepsy.

Progression of Endolymphatic Hydrops in Meniere's Disease as Evaluated by Magnetic Resonance Imaging

Objective: To evaluate the presence and the degree of endolymphatic hydrops (EHs) in patients with unilateral Ménières disease (MD), as a function of duration of the disease, estimated using a 3-dimensional fluid-attenuated inversion recovery sequence in a 3-Tesla magnetic resonance imaging unit, after intratympanic gadolinium administration. Patients: A total of 32 patients (21 male and 11 female subjects, aged 25-78 yr; median, 56 yr) participated in the investigation. The duration of the disease ranged from 2 months to 10 years (median, 3 yr), with a prevalence of vertigo spells in the last 6 months ranging from 0.5 to 8 per month (median, 2.5). Intervention: A 0.6-ml solution of gadobutrol (1 mmol/ml) diluted 1:7 in saline was injected in the affected ear through the inferior-posterior quadrant of the tympanic membrane, using a 22-gauge spinal needle. The patient was kept with the head rotated 45 degrees contralaterally for 30 minutes after each injection. Twenty-four hours later, a 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging was performed. Main Outcome Measure: Perilymphatic enhancement was evaluated in different portions of the labyrinth as a function of MD duration. Results: Reduced or absence of enhancement of the vestibule occurred precociously and occurred in all subjects at long term. The prevalence of enhancement abnormalities in the cochlea and the semicircular canals was directly proportional to MD duration. At long term, the vestibule and the cochlea showed a more severe hydropic involvement compared with semicircular canals. A statistical significant correlation between enhancement abnormalities and MD duration was observed for most inner ear sites. Conclusion: The increased prevalence and severity of EH with the duration of MD indicates that hydrops is a progressive degenerative phenomenon. The frequent abnormality in the vestibule and, secondarily, in the cochlea is in line with some histopathologic investigations. It remains to be clarified whether hydropic changes are related to specific signs and symptoms of MD.

Magnetic resonance imaging fails to show evidence of reduced endolymphatic hydrops in gentamicin treatment of Ménière's disease.

Objective To verify the hypothesis that intratympanic (IT) gentamicin (Gent) treatment in Ménière’s disease (MD) is capable of reducing endolymphatic hydrops (EH), as evaluated by 3-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequence in a 3-Tesla magnetic resonance imaging (MRI) unit, after IT gadolinium administration. Patients A total of 8 patients (5 men and 3 women; aged 40–78 yr; median, 60 yr) with definite MD participated in the investigation. The duration of the disease ranged from 1 to 10 years (median, 4 yr), with a prevalence of vertigo spells of 1 to 6 per month (median, 3.1), as calculated in the last 6 months. Intervention A 3D-FLAIR MRI was performed 24 hours after IT injection of diluted gadobutrol. Intratympanic Gent injection was performed in a period variable from 1 to 3 weeks after 3D-FLAIR MRI. A single-shot administration protocol was attempted with additional injections administered on demand in the case of relapsing vertigo spells. MRI was repeated after 3 to 12 months (median, 8 mo) after treatment. Main Outcome Measure The degree and extension of EH as evaluated by 3D-FLAIR MRI was compared from images obtained pre- and post-ITGent administration. Results After ITGent administration, 4 patients did not show any MRI modification, 3 patients showed a worsening of EH in one site, and 1 patient showed a worsening in two sites. No subjects presented reduction of EH. Conclusion No evidence of reduced EH following ITGent treatment has been shown in the present imaging investigation.

Mapping the Structural Brain Changes in Alzheimer's Disease: The Independent Contribution of Two Imaging Modalities

The macrostructural atrophy of Alzheimers disease (AD) has been fully described. Current literature reports that also microstructural alterations occur in AD since the early stages. However, whether the microstructural changes offer unique information independent from macrostructural atrophy is unclear. Aim of this study is to define the independent contribution of macrostructural atrophy and microstructural alterations on AD pathology. The study involved 17 moderate to severe AD patients and 13 healthy controls. All participants underwent conventional and non conventional MRI (respectively, T1-weighted and diffusion-weighted MR scanning). We processed the images in order to obtain gray and white matter volumes to assess macrostructural atrophy, and fractional anisotropy and mean diffusivity to assess the microstructural damage. Analyses of covariance between patients and controls were performed to investigate microstructural tissue damage independent of macrostructural tissue loss, and vice versa, voxel by voxel. We observed microstructural differences, independent of macrostructural atrophy, between patients and controls in temporal and retrosplenial regions, as well as in thalamus, corticopontine tracts, striatum and precentral gyrus. Volumetric differences, independent of microstructural alterations, were observed mainly in the entorhinal cortex, posterior cingulum, and splenium. Measures of microstructural damage provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD as well as in others thought to be spared. This work expands the understanding of the topography of pathological changes in AD that can be captured with imaging techniques.