Eric Jouvent

Determinants of iron accumulation in the normal aging brain

In a recent postmortem study, R2* relaxometry in gray matter (GM) of the brain has been validated as a noninvasive measure for iron content in brain tissue. Iron accumulation in the normal aging brain is a common finding and relates to brain maturation and degeneration. The goal of this study was to assess the determinants of iron accumulation during brain aging. The study cohort consisted of 314 healthy community-dwelling participants of the Austrian Stroke Prevention Study. Their age ranged from 38-82xa0years. Quantitative magnetic resonance imaging was performed on 3T and included R2* mapping, based on a 3D multi-echo gradient echo sequence. The median of R2* values was measured in all GM regions, which were segmented automatically using FreeSurfer. We investigated 25 possible determinants for cerebral iron deposition. These included demographics, brain volume, lifestyle factors, cerebrovascular risk factors, serum levels of iron, and single nucleotide polymorphisms related to iron regulating genes (rs1800562, rs3811647, rs1799945, and rs1049296). The body mass index (BMI) was significantly related to R2* in 15/32 analyzed brain regions with the strongest correlations found in the amygdala (pxa0= 0.0091), medial temporal lobe (pxa0= 0.0002), and hippocampus (p ≤ 0.0001). Further associations to R2* values were found in deep GM for age and smoking. No significant associations were found for gender, GM volume, serum levels of iron, or iron-associated genetic polymorphisms. In conclusion, besides age, the BMI and smoking are the only significant determinants of brain iron accumulation in normally aging subjects. Smoking relates to iron deposition in the basal ganglia, whereas higher BMI is associated with iron content in the neocortex following an Alzheimer-like distribution.

In Vivo High-Resolution 7 Tesla MRI Shows Early and Diffuse Cortical Alterations in CADASIL

Background and Purpose Recent data suggest that early symptoms may be related to cortex alterations in CADASIL (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a monogenic model of cerebral small vessel disease (SVD). The aim of this study was to investigate cortical alterations using both high-resolution T2* acquisitions obtained with 7 Tesla MRI and structural T1 images with 3 Tesla MRI in CADASIL patients with no or only mild symptomatology (modified Rankin’s scale ≤1 and Mini Mental State Examination (MMSE) ≥24). Methods Complete reconstructions of the cortex using 7 Tesla T2* acquisitions with 0.7 mm isotropic resolution were obtained in 11 patients (52.1±13.2 years, 36% male) and 24 controls (54.8±11.0 years, 42% male). Seven Tesla T2* within the cortex and cortical thickness and morphology obtained from 3 Tesla images were compared between CADASIL and control subjects using general linear models. Results MMSE, brain volume, cortical thickness and global sulcal morphology did not differ between groups. By contrast, T2* measured by 7 Tesla MRI was significantly increased in frontal, parietal, occipital and cingulate cortices in patients after correction for multiple testing. These changes were not related to white matter lesions, lacunes or microhemorrhages in patients having no brain atrophy compared to controls. Conclusions Seven Tesla MRI, by contrast to state of the art post-processing of 3 Tesla acquisitions, shows diffuse T2* alterations within the cortical mantle in CADASIL whose origin remains to be determined.

Decreased T1 Contrast between Gray Matter and Normal-Appearing White Matter in CADASIL

BACKGROUND AND PURPOSE: CADASIL is the most frequent hereditary small-vessel disease of the brain. The clinical impact of various MR imaging markers has been repeatedly studied in this disorder, but alterations of contrast between gray matter and normal-appearing white matter remain unknown. The aim of this study was to evaluate the contrast alterations between gray matter and normal-appearing white matter on T1-weighted images in patients with CADASIL compared with healthy subjects. MATERIALS AND METHODS: Contrast between gray matter and normal-appearing white matter was assessed by using histogram analyses of 3D T1 high-resolution MR imaging in 23 patients with CADASIL at the initial stage of the disease (Mini-Mental State Examination score > 24 and modified Rankin scale score ≤ 1; mean age, 53.5 ± 11.1 years) and 30 age- and sex-matched controls. RESULTS: T1 contrast between gray matter and normal-appearing white matter was significantly reduced in patients compared with age- and sex-matched controls (patients: 1.35 ± 0.08 versus controls: 1.43 ± 0.04, P < 10−5). This reduction was mainly driven by a signal decrease in normal-appearing white matter. Contrast loss was strongly related to the volume of white matter hyperintensities. CONCLUSIONS: Conventional 3D T1 imaging shows significant loss of contrast between gray matter and normal-appearing white matter in CADASIL. This probably reflects tissue changes in normal-appearing white matter outside signal abnormalities on T2 or FLAIR sequences. These contrast alterations should be taken into account for image interpretation and postprocessing.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients.

Alterations of the cerebral cortex in sporadic small vessel disease: A systematic review of in vivo MRI data.

Cerebral small vessel diseases of the brain are a major determinant of cognitive impairment in the elderly. In small vessel diseases, the most easily identifiable lesions, both at post-mortem evaluation and magnetic resonance imaging, lie in subcortical areas. However, recent results obtained post-mortem, particularly in severe cases, have highlighted the burden of cortex lesions such as microinfarcts and diffuse neuronal loss. The recent development of image post-processing methods allows now assessing in vivo multiple aspects of the cerebral cortex. This systematic review aimed to analyze in vivo magnetic resonance imaging studies evaluating cortex alterations at different stages of small vessel diseases. Studies assessing the relationships between small vessel disease magnetic resonance imaging markers obtained at the subcortical level and cortex estimates were reviewed both in community-dwelling elderly and in patients with symptomatic small vessel diseases. Thereafter, studies analyzing cortex estimates in small vessel disease patients compared with healthy subjects were evaluated. The results support that important cortex alterations develop along the course of small vessel diseases independently of concomitant neurodegenerative processes. Easy detection and quantification of cortex changes in small vessel diseases as well as understanding their underlying mechanisms are challenging tasks for better understanding cognitive decline in small vessel diseases.

A rare cause of gait ataxia

In November, 2010, a 57-year-old man was referred to us with a 2-month history of gait ataxia and sudden deafness. He had been healthy until February, 2010, when he started to have recurrent episodes of redness and discomfort aff ecting his eyes in an alternating manner, lasting several days. Ophthalmologists diagnosed conjunctivitis and eyedrops were prescribed. The patient’s wife had noticed that on occasion his right ear was red, hot, and swollen for several days, either associated with redness in the eyes or independently. On Oct 20, 2010, the patient suddenly experienced vertigo and ataxia, without nausea, vomiting, tinnitus, or hearing loss. Although the vertigo subsided within 10 days, gait ataxia worsened. Oral steroids were prescribed by an ENT specialist for 1 week with some functional improvement, and subsequently stopped. On Nov 13, 2010, the patient experienced sudden bilateral deafness with tinnitus and returned to see his ENT specialist. On examination, he had bilateral sensorineural deafness, more pronounced on the right side, and bilateral vestibular arefl exia. Cogan syndrome (a rare disorder characterised by non-syphilitic interstitial keratitis and vestibuloauditory symptoms) was initially suspected, but this diagnosis was thought unlikely in the absence of interstitial keratitis at the various ophthalmological examinations done in the preceding months. A neurology consultation was sought because of the patient’s abnormal gait. It was noted that he had a widebased, unsteady gait, mimicking a cerebellar gait, but without any other cerebellar signs eg, dysarthria, ocular ataxia, nystagmus, or limb dysmetria. Romberg sign was negative. Apart from profound deafness, neurological examination was otherwise normal. His right ear was noted to be hot, red, swollen, and tender (fi gure A). Brain MRI with FLAIR, diff usion, T1, and T2 sequences, and MR angiography were normal. A diagnosis of relapsing polychondritis was considered. Laboratory test results showed leucocytosis and the presence of antinuclear antibodies. Diagnosis was confi rmed by biopsy of ear cartilage; the sample showed necrosis of the cartilage matrix and perichondral infl ammation with lymphocytic and plasmocytic infi ltrate—a pattern that is quite specifi c to the disease. Retrospectively, ear oedema was visible on diff usion MRI (fi gure B). Three criteria for relapsing polychondritis, including positive histopathological fi ndings, were present. Oral prednisone 1 mg/kg daily was started immediately, resulting in improvement of deafness and tinnitus over the next few days. Gait ataxia improved more slowly. The patient was able to resume work 2 months after steroids were initiated. When last seen in April, 2011, a slight unsteadiness in gait persisted. Relapsing polychondritis is a rare disorder with an incidence around 3·5 cases per million, characterised by deterioration of cartilage, often aff ecting that of ears, nose, throat, ribs, or heart valves. By contrast to auditory loss, vestibular dysfunction is rare in relapsing polychondritis and was the initial symptom in only one of 23 cases. Usual manifestations are auricular and nasal chondritis, arthritis, ocular infl ammation, and laryngotracheal symptoms before vestibulocochlear dysfunction. In relapsing polychondritis, vestibular dysfunction can be secondary to chondritis-induced destruction of the eustachian tube leading to infl ammation of the inner ear. Vasculitis of vestibulocochlear arteries can also be involved, either primarily or secondary to an associated systemic disease, such as systemic lupus erythematosus. Prognosis predominantly depends on airway involvement, infection, and cardiovascular compli cations; 10-year mortality varies between 5% and 50%. Treatment is with oral corticosteroids. Our case shows that gait ataxia due to bilateral vestibular arefl exia can mimic cerebellar gait ataxia. It also reinforces the point that health-care professionals should listen carefully to patients and their relatives for clues in making a diagnosis.

Cerebral Microhemorrhages: Significance, Associations, Diagnosis, and Treatment.

Opinion statementCerebrovascular pathologies expose patients to both ischemic and hemorrhagic risks. Given the progressive aging of populations, more and more patients will experience both types of events during their lifetime. The generalization of brain magnetic resonance imaging as a first-line imaging modality for evaluating patients with cerebrovascular diseases has led to the need to manage new types of imaging information about the cerebral tissue, such as the presence, location, and number of cerebral microhemorrhages (CMs). Originally, CMs were thought to be merely spatially localized distortions of the image, mostly secondary to foci of iron deposition within the brain parenchyma. During the past 20xa0years, however, innumerable research studies have demonstrated that these small foci of signal loss, presumably related to a circumscribed rupture of small vessels, may be used to better estimate the balance between hemorrhagic and ischemic risks. We are now entering the era of personalized medicine, in which treatment decisions are adjusted for each patient according to various genetic, biological, or imaging data. Therefore, integrating CMs into patient management at the individual level will be crucial in the future. This review aims to deliver some clues to interpret the impact of CMs on our clinical decisions.

Free water determines diffusion alterations and clinical status in cerebral small vessel disease

Diffusion tensor imaging detects early tissue alterations in Alzheimers disease and cerebral small vessel disease (SVD). However, the origin of diffusion alterations in SVD is largely unknown.

Why Are Only Some Subcortical Ischemic Lesions on Diffusion Magnetic Resonance Imaging Associated With Stroke Symptoms in Small Vessel Disease

Background and Purpose— In cerebral small vessel diseases, small subcortical ischemic lesions (SSIL) on diffusion imaging are responsible for stroke manifestations but can also be occasionally observed in the absence of overt neurological symptoms. We aimed to determine, in a large cohort of young patients with CADASIL (Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic condition leading to SSIL in young patients, the characteristics of SSIL and of surrounding cerebral tissue associated with the presence of stroke symptoms. Methods— Among a cohort of 323 genetically confirmed CADASIL patients who were systematically evaluated every 18 months clinically and with magnetic resonance imaging, we studied all visible SSIL and documented ischemic stroke events with available magnetic resonance imaging data. We used mixed-effect logistic regression models to determine whether the presence of stroke symptoms was associated with age, sex, the volume of SSIL, their location with respect to preexisting white matter hyperintensities and with the load of the different magnetic resonance imaging markers of small vessel disease. Results— We identified 73 SSIL (30 with stroke symptoms and 43 without) in 55 patients. In multivariable models, stroke symptoms were more frequent in male patients (estimate=1.94; SE=0.82; P=0.03) and less frequent when SSIL appeared in contact to preexisting white matter hyperintensities (estimate=−2.12; SE=0.83; P=0.01). Within pyramidal tracts, stroke symptoms were more frequent in patients with extensive white matter hyperintensities (estimate=3.8×10−5; SE=9.3×10−6; P<10−4). Conclusions— Altogether, our results suggest that when SSIL occur, the presence of stroke symptoms may depend on sex and alterations of the surrounding brain tissue rather than on the characteristics of the SSIL itself.

Validation and Optimization of BIANCA for the Segmentation of Extensive White Matter Hyperintensities.

White matter hyperintensities (WMH) are a hallmark of small vessel diseases (SVD). Yet, no automated segmentation method is readily and widely used, especially in patients with extensive WMH where lesions are close to the cerebral cortex. BIANCA (Brain Intensity AbNormality Classification Algorithm) is a new fully automated, supervised method for WMH segmentation. In this study, we optimized and compared BIANCA against a reference method with manual editing in a cohort of patients with extensive WMH. This was achieved in two datasets: a clinical protocol with 90 patients having 2-dimensional FLAIR and an advanced protocol with 66 patients having 3-dimensional FLAIR. We first determined simultaneously which input modalities (FLAIR alone or FLAIR + T1) and which training sets were better compared to the reference. Three strategies for the selection of the threshold that is applied to the probabilistic output of BIANCA were then evaluated: chosen at the group level, based on Fazekas score or determined individually. Accuracy of the segmentation was assessed through measures of spatial agreement and volumetric correspondence with respect to reference segmentation. Based on all our tests, we identified multimodal inputs (FLAIR + T1), mixed WMH load training set and individual threshold selection as the best conditions to automatically segment WMH in our cohort. A median Dice similarity index of 0.80 (0.80) and an intraclass correlation coefficient of 0.97 (0.98) were obtained for the clinical (advanced) protocol. However, Bland-Altman plots identified a difference with the reference method that was linearly related to the total burden of WMH. Our results suggest that BIANCA is a reliable and fast segmentation method to extract masks of WMH in patients with extensive lesions.