R. Della Nave

Whole-Brain Histogram and Voxel-Based Analyses of Diffusion Tensor Imaging in Patients with Leukoaraiosis: Correlation with Motor and Cognitive Impairment

BACKGROUND AND PURPOSE: Cerebral white matter changes, termed leukoaraiosis (LA), appearing as areas of increased signal intensity in T2-weighted MR images, are common in elderly subjects, but the possible correlation of LA with cognitive or motor deficit has not been established. We hypothesized that histogram and voxel-based analyses of whole-brain mean diffusivity (MD) and fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) could be more sensitive tools than visual scales to investigate the clinical correlates of LA. MATERIALS AND METHODS: Thirty-six patients of the Leukoaraiosis and Disability Study were evaluated with fluid-attenuated inversion recovery for LA extension, T1-weighted images for volume, and DTI for MD and FA. The extent of LA was rated visually. The normalized total, gray, and white matter brain volumes were computed, as well as the 25th percentile, 50th percentile, kurtosis, and skewness of the MD and FA maps of the whole brain. Finally, voxel-based analysis on the maps of gray and white matter volume, MD, and FA was performed with SPM2 software. Correlation analyses between visual or computerized data and motor or neuropsychologic scale scores were performed using the Spearman rank test and the SPM2 software. RESULTS: The visual score correlated with some MD and FA histogram metrics (P < .01). However, only the 25th and 50th percentiles, kurtosis, and skewness of the MD and FA histograms correlated with motor or neuropsychologic deficits. Voxel-based analysis revealed a correlation (P < .05 corrected for multiple comparisons) between a large cluster of increased MD in the corpus callosum and pericallosal white matter and motor deficit. CONCLUSIONS: These results are consistent with the hypothesis that histogram and voxel-based analyses of the whole-brain MD and FA maps are more sensitive tools than the visual evaluation for clinical correlation in patients with LA.

Regional Distribution and Clinical Correlates of White Matter Structural Damage in Huntington Disease: A Tract-Based Spatial Statistics Study

BACKGROUND AND PURPOSE: HD entails damage of the WM. Our aim was to explore in vivo the regional volume and microstructure of the brain WM in HD and to correlate such findings with clinical status of the patients. MATERIALS AND METHODS: Fifteen HD gene carriers in different clinical stages of the disease and 15 healthy controls were studied with T1-weighted images for VBM and DTI for TBSS. Maps of FA, MD, and λ∥ and λ⊥ were reconstructed. RESULTS: Compared with controls, in addition to neostriatum and cortical GM volume loss, individuals with HD showed volume loss in the genu of the internal capsule and subcortical frontal WM bilaterally, the right splenium of the corpus callosum, and the left corona radiata. TBSS revealed symmetrically decreased FA in the corpus callosum, fornix, external/extreme capsule, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus. Areas of increased MD were more extensive and included arciform fibers of the cerebral hemispheres and cerebral peduncles. Increase of the λ∥ and a comparatively more pronounced increase of the λ⊥ underlay the decreased FA of the WM in HD. Areas of WM atrophy, decreased FA, and increased MD correlated with the severity of the motor and cognitive dysfunction, whereas only the areas with increased MD correlated with disease duration. CONCLUSIONS: Microstructural damage accompanies volume decrease of the WM in HD and is correlated with the clinical deficits and disease duration. MR imaging−based measures could be considered as a biomarker of neurodegeneration in HD gene carriers.

Brain structural damage in Friedreich’s ataxia

Objective: Neuropathological descriptions of the brain in Friedreich’s ataxia (FRDA) were obtained before availability of the current molecular genetic tests for this disease. Voxel-based morphometry (VBM) enables an unbiased whole-brain quantitative analysis of differences in gray matter (GM) and white matter (WM) volume. Methods: Using VBM, we assessed the brain structural damage in 22 patients with genetically confirmed FRDA and 25 healthy controls. The results were correlated with the disease duration and the severity of the patients’ clinical deficits—evaluated using the International Cerebellar Ataxia Rating Scale and Inherited Ataxia Clinical Rating Scale. Results: In patients with FRDA, VBM showed a symmetrical volume loss in dorsal medulla, infero-medial portions of the cerebellar hemispheres, the rostral vermis and in the dentate region. No volume loss in cerebral hemispheres was observed. The atrophy of the cerebellum and medulla correlated with the severity of the clinical deficit and disease duration. Conclusions: In patients with FRDA, significant GM and WM loss was observed only in the cerebellum and dorsal medulla. These structural changes correlate with the severity of the clinical deficit and disease duration.

A Whole-Brain Analysis in De Novo Parkinson Disease

BACKGROUND AND PURPOSE: Widespread cerebral changes are observed in advanced stages of Parkinson disease (PD), suggesting that PD is a multisystem disorder. We investigated with MR imaging whether global brain changes are present in early clinical stages of PD and correlated the findings with the type of clinical presentation. MATERIALS AND METHODS: T1-weighted images and mean diffusivity and fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) were obtained in 27 patients with de novo drug-naïve PD, who were classified according to the clinical features in tremor-dominant type (n = 13), akinetic-rigid type (n = 11), and mixed type (n = 3). Sixteen healthy subjects provided control data. With SIENAX software, total brain, gray matter (GM), and white matter (WM) volumes were computed from T1-weighted images, whereas brain histograms were obtained from mean diffusivity and FA maps. RESULTS: Total brain, GM and WM volumes were not significantly different in patients as a whole or subgroups and controls. As compared with controls, patients with PD as a whole and patients with the akinetic-rigid type showed an increase (P ≤ .01) of the twenty-fifth percentile of the FA histogram. In patients with the akinetic-rigid type, there also was a trend toward an increase of the mean and fiftieth and seventy-fifth percentiles, and a reduction of the skewness of the FA histogram. Patients with tremor-dominant type showed a trend toward an increase of the twenty-fifth percentile of the FA histogram. CONCLUSIONS: In patients with de novo PD, there is an increase of FA values, more pronounced in patients with the akinetic-rigid type, probably reflecting diffuse subtle GM loss. This is in line with the hypothesis that widespread neurodegeneration is already present at the time of the clinical onset.

Early structural changes in individuals at risk of familial Alzheimer’s disease: a volumetry and magnetization transfer MR imaging study

Presenilin 1 (PS1) mutation carriers provide the opportunity to asses early features of neurodegeneration in familial Alzheimer’s disease (AD). Gray matter (GM) regional volume loss and decrease of magnetization transfer ratio (MTR) consistent with microstructural changes have been reported in sporadic AD. We performed a regional volumetric and MTR analysis in carriers of PS1 mutations. Six non-demented mutated PS1 carriers (5 with memory deficits) and 14 healthy subjects were examined with high resolution T1-weighted images for volumetry and with T2* weighted images for MTR. Cortical GM volume and MTR values were derived. Compared to healthy controls, the GM volume of the left temporal and inferior parietal cortex and the MTR of the temporal cortex bilaterally were significantly decreased in PS1 gene carriers. In the latter, the temporal lobe MTR showed a trend for correlation with memory and executive function scores. Early neurodegeneration in non-demented subjects at risk for familial AD may be associated with atrophy and decreased MTR in the temporal cortex.

Paroxysmal arousal in epilepsy associated with cingulate hyperperfusion.

A patient with nocturnal frontal lobe epilepsy characterized by paroxysmal motor attacks during sleep had brief paroxysmal arousals (PAs), complex episodes of nocturnal paroxysmal dystonia, and epileptic nocturnal wandering since childhood. Ictal SPECT during an episode of PA demonstrated increased blood flow in the right anterior cingulate gyrus and cerebellar cortex with hypoperfusion in the right temporal and frontal associative cortices.

STRUCTURAL ANOMALY OF LEFT LATERAL TEMPORAL LOBE IN EPILEPSY DUE TO MUTATED LGI1

Autosomal dominant lateral temporal epilepsy (ADTLE) is a syndrome characterized by ictal auditory phenomena suggesting a lateral temporal lobe seizure onset and is associated with mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene.1,2 The structure of the LGI1 protein includes, in the N-terminal portion, three leucine-rich repeats (LRR). The function of LGI1 and the mechanisms underlying epilepsy in patients with LGI1 mutations are not established. However, LGI1 is involved in the control of survival of neuroblastoma cell lines.3 This feature and the structural homology between LGI1 and other LRR proteins essential for the development of the CNS3 make it conceivable that LGI1 mutations could imply some structural abnormalities of the lateral temporal lobe as the substratum underlying partial epilepsy in ADTLE. Neuropathologic data are lacking and conventional MRI studies failed to show consistent findings in ADTLE.1,2 Voxel-based analyses enable detection of subtle regional differences in MR images.4,5 ### Methods. We performed voxel-based analyses of T1-weighted, diffusion-tensor, and magnetization transfer (MT) images of the brain in 8 patients (3 women and 5 men, mean age 49 ± 13 years) with ADTLE and LGI1 mutations and 24 healthy control subjects (14 women and 10 men, mean …

Brain structural damage in spinocerebellar ataxia type 1 : a VBM study.

Background and objectiveNeuropathological description of the brain in spinocerebellar ataxia type 1(SCA1) is limited to a few cases. Voxel-based morphometry (VBM) enables an unbiased in vivo whole-brain quantitative analysis of regional differences in gray matter (GM) and white matter (WM) volume. We assessed with VBM the structural damage in patients with genetically confirmed SCA1.MethodFifteen SCA1 patients and 15 age-matched healthy controls underwent MR examination with acquisition of high-resolution T1-weighted images. The results were correlated with the disease duration and severity of the clinical deficit assessed with the International Cerebellar Ataxia Rating Scale (ICARS) and Inherited Ataxia Clinical Rating Scale (IACRS).ResultsAs compared to controls, patients with SCA1 showed a significant (p < 0.05 corrected for multiple comparison) symmetric loss of volume of the GM in the rostral cerebellar vermis and paramedian portions of the anterior cerebellar lobes. WM was decreased in the peridentate region and middle cerebellar peduncles but not in the pons. No GM or WM volume loss was found in the cerebral hemispheres. The cerebellar and brainstem GM and WM volume loss correlated with disease duration and the ICARS and IACRS scores.ConclusionsVBM confirms that atrophy predominantly involves the brainstem and cerebellum in SCA1. The correlation with the clinical features indicates that VBM might be useful to monitor disease progression.

MRI and SPECT of midbrain and striatal degeneration in fragile X-associated tremor/ataxia syndrome

Sirs: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inclusion disorder with an estimated prevalence among men > 50 years of age up to 1 in 3000 in the general population [16]. The neurologic phenotype of FXTAS is variable and includes intention tremor, ataxia, parkinsonism, and cognitive decline [7–10]. We report evidence from MRI and SPECT that the fragile X premutation determines a subcortical gray matter degeneration involving the midbrain and striatum associated with parkinsonian signs. We studied five men with FXTAS and documentation of the premutation by DNA testing whose genetic and clinical data are detailed in Table 1. In all patients prior MRI showed characteristic symmetric areas of signal changes in the peridentate, middle cerebellar peduncle and cerebral white matter and diffuse brain atrophy [2, 5]. MRI was obtained in patients 1, 2, 4 and 5 at 1.5 T with a protocol including 1 mm thick T1-weighted 3D gradient echo images and 5 mm thick T2-weighted spin-echo (SE) images for evaluation of hypointensities suggestive for possible iron deposits in the basal ganglia [6, 14]. Bulk and shape of the midbrain were evaluated subjectively [12] and midbrain anteroposterior diameter was measured in patients and in 12 healthy subjects [15]. Basal ganglia signals in T2-weighted SE images were visually assessed. Midbrain evaluation in case 4 was performed on hard copies of prior MRI. SPECT examinations were obtained in patients 1, 3–5. They were injected with 111–185 MBq of [123I]FP-CIT for evaluation of striatal dopamine transporter (DAT) density. Patient 3 was also injected with 160 MBq of [123I] idobenzamide (IBZM) for evaluation of striatal dopamine D2 receptors. SPECT examinations were evaluated visually [1]. MRI and SPECT findings are reported in Table 1. Atrophy of the midbrain with an AP diameter smaller than 17 mm [15] was observed in all patients. The superior profile of the midbrain was concave in two patients (Fig. 1) and linear in three. Symmetric hypointensity in the putamen and caudate in T2-weighted SE images was present in all four patients examined with the protocol. DATscan SPECT in patients 3, 4 and 5 showed an asymmetric decrease of the striatum tracer uptake which was mild in cases 4 and 5 and marked in case 3 (Fig. 1). IBZM SPECT in patient 3 revealed almost complete absence of striatal tracer uptake (Fig. 1) Parkinsonism is one of the most common other diagnoses given to FXTAS patients which also include tremor, ataxia, dementia or stroke [9] and fragile X premutation is found in 4 % of patients with diagnosis of probable multi-system atrophy cerebellar type (MSA-C) [10]. Neuropathological examination in FXTAS demonstrates, along with spongiosis of the white matter, nuclear eosinophilic inclusions in the neurons and astrocytes of the cortical and subcortical gray matter, including the substantia nigra and putamen, of possible pathogenetic role [7]. We found MRI evidence of midbrain and striatal neurodegeneration in five patients with FXTAS who showed extra-pyramidal signs. Three patients had vertical gaze palsy, namely a feature of midbrain involvement which is not observed in Parkinson disease (PD) and is characteristic of progressive supranuclear palsy (PSP). In particular, we measured atrophy of the midbrain in all five FXTAS patients that was accompanied by a concave or linear superior profile of the midbrain, instead of the convex profile observed in healthy subjects [12]. These features were emphasized as distinctive of PSP [12, 15]. It is noteworthy that also in LETTER TO THE EDITORS

Magnetization transfer MR imaging demonstrates degeneration of the subcortical and cortical gray matter in Huntington disease.

BACKGROUND AND PURPOSE: GM is typically affected in HD since the presymptomatic stage. Our aim was to investigate with MT MR imaging the microstructural changes of the residual brain subcortical and cortical GM in carriers of the HD gene and to preliminarily assess their correlation with the clinical features. MATERIALS AND METHODS: Fifteen HD gene carriers with a range of clinical severity and 15 age- and sex-matched healthy controls underwent MT MR imaging on a 1.5T scanner. The MT ratio was measured automatically in several subcortical and cortical GM regions (striatal nuclei; thalami; and the neocortex of the frontal, temporal, parietal, and occipital lobes) by using FLS tools. RESULTS: The MT ratio was significantly (P < .05 with Bonferroni correction for multiple comparison) decreased in all subcortical structures except the putamen and decreased diffusely in the cerebral cortex of HD carriers compared with controls. Close correlation was observed between the subcortical and cortical regional MT ratios and several clinical variables, including disease duration, motor disability, and scores in timed neuropsychological tests. CONCLUSIONS: MT imaging demonstrates degeneration of the subcortical and cortical GM in HD carriers and might serve, along with volumetric assessment, as a surrogate marker in future clinical trials of HD.