Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study.

Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81-0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.

A common low dimensional structure of cognitive impairment in stroke and brain tumors.

INTRODUCTION: Neuropsychological studies infer brain-behavior relationships from focal lesions like stroke and tumors. However, these pathologies impair brain function through different mechanisms even when they occur at the same brain's location. The aim of this study was to compare the profile of cognitive impairment in patients with brain tumors vs. stroke and examine the correlation with lesion location in each pathology. METHODS: Patients with first time stroke (n = 77) or newly diagnosed brain tumors (n = 76) were assessed with a neuropsychological battery. Their lesions were mapped with MRI scans. Test scores were analyzed using principal component analysis (PCA) to measure their correlation, and logistic regression to examine differences between pathologies. Next, with ridge regression we examined whether lesion features (location, volume) were associated with behavioral performance. RESULTS: The PCA showed a similar cognitive impairment profile in tumors and strokes with three principal components (PCs) accounting for about half of the individual variance. PC1 loaded on language, verbal memory, and executive/working memory; PC2 loaded on general performance, visuo-spatial attention and memory, and executive functions; and, PC3 loaded on calculation, reading and visuo-spatial attention. The average lesion distribution was different, and lesion location was correlated with cognitive deficits only in stroke. Logistic regression found language and calculation more affected in stroke, and verbal memory and verbal fluency more affected in tumors. CONCLUSIONS: A similar low dimensional set of behavioral impairments was found both in stroke and brain tumors, even though each pathology caused some specific deficits in different domains. The lesion distribution was different for stroke and tumors and correlated with behavioral impairment only in stroke.

Quantification of normal-appearing white matter damage in early relapse-onset multiple sclerosis through neurite orientation dispersion and density imaging.

Background Neurodegeneration is a major contributor of neurological disability in multiple sclerosis (MS). The possibility to fully characterize normal appearing white matter (NAWM) damage could provide the missing information needed to clarify the mechanisms beyond disability accumulation. Objective In the present study we aimed to characterize the presence and extent of NAWM damage and its correlation with clinical disability. Methods We applied Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) in a cohort of 27 early relapse-onset MS patients (disease duration < 5 years) compared to a population of 26 age- and sex-matched healthy controls (HCs). All patients underwent a neurological examination, including the Expanded Disability Status Scale (EDSS). Results MS patients showed lower fractional anisotropy (FA) and higher mean diffusivity (MD) values in the main WM bundles, such as the corticospinal tract, corpus callosum, superior and middle cerebellar peduncles, posterior thalamic radiation (which includes optic radiation), cingulum and external capsule. All brain areas with reduced FA/increased MD also displayed a reduction in neurite density index (NDI). However, comparing individual voxels of the WM skeleton between MS and HCs, a higher number of NDI significant voxels was disclosed compared to FA/MD (56.4% vs 11.2%/41.2%). No significant correlations were observed between DTI/NODDI metrics and EDSS. Conclusions Our findings suggest that NDI may allow for a better characterization and understanding of the microstructural changes in the NAWM since the early relapsing-remitting MS phases. Future longitudinal studies including a larger cohort of patients with different clinical phenotypes may clarify the association between NODDI metrics and disability progression.

PET/MR in recurrent glioblastoma patients treated with regorafenib: [18F]FET and DWI-ADC for response assessment and survival prediction.

OBJECTIVE: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. Diffusion-weighted imaging and O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in diffusion-weighted imaging/apparent diffusion coefficient (ADC) and [18F]FET PET-derived parameters in patients who underwent PET/MR at both baseline and after starting regorafenib. METHODS: We retrospectively reviewed 16 consecutive GBM patients who underwent [18F]FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze four SD patients who underwent a third PET/MR after another four cycles of regorafenib. [18F]FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and after treatment. Several metrics were then derived and compared. Log-rank test was applied for overall survival analysis. RESULTS: Percentage difference in FET volumes correlates with the corresponding percentage difference in ADC (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Kaplan-Meier analysis, performed to compare the performance in overall survival prediction, revealed that the percentage variations of FET- and ADC-derived metrics performed at least as well as RANO criteria (p = 0.02, p = 0.024 and p = 0.04 respectively) and in some cases even better. TBR Max and TBR mean are not able to accurately predict overall survival. CONCLUSION: In recurrent glioblastoma patients treated with regorafenib, [18F]FET and ADC metrics, are able to predict overall survival and being obtained from completely different measures as compared to RANO, could serve as semi-quantitative independent biomarkers of response to treatment. ADVANCES IN KNOWLEDGE: Simultaneous evaluation of [18F]FET and ADC metrics using PET/MR allows an early and reliable identification of response to treatment and predict overall survival.

Early red nucleus atrophy in relapse-onset multiple sclerosis.

No study has investigated red nucleus (RN) atrophy in multiple sclerosis (MS) despite cerebellum and its connections are elective sites of MS-related pathology. In this study, we explore RN atrophy in early MS phases and its association with cerebellar damage (focal lesions and atrophy) and physical disability. Thirty-seven relapse-onset MS (RMS) patients having mean age of 35.6 ± 8.5 (18-56) years and mean disease duration of 1.1 ± 1.5 (0-5) years, and 36 age- and sex-matched healthy controls (HC) were studied. Cerebellar and RN lesions and volumes were analyzed on 3 T-MRI images. RMS did not differ from HC in cerebellar lobe volumes but significantly differed in both right (107.84 ± 13.95 mm3 vs. 99.37 ± 11.53 mm3 , p = .019) and left (109.71 ± 14.94 mm3 vs. 100.47 ± 15.78 mm3 , p = .020) RN volumes. Cerebellar white matter lesion volume (WMLV) inversely correlated with both right and left RN volumes (r = -.333, p = .004 and r = -.298, p = .010, respectively), while no correlation was detected between RN volumes and mean cortical thickness, cerebellar gray matter lesion volume, and supratentorial WMLV (right RN: r = -.147, p = .216; left RN: r = -.153, p = .196). Right, but not left, RN volume inversely correlated with midbrain WMLV (r = -.310, p = .008), while no correlation was observed between whole brainstem WMLV and either RN volumes (right RN: r = -.164, p = .164; left RN: r = -.64, p = .588). Finally, left RN volume correlated with vermis VIIb (r = .297, p = .011) and right interposed nucleus (r = .249, p = .034) volumes. We observed RN atrophy in early RMS, likely resulting from anterograde axonal degeneration starting in cerebellar and midbrain WML. RN atrophy seems a promising marker of neurodegeneration and/or cerebellar damage in RMS.

Cerebellar gray matter lesions are common in pediatric multiple sclerosis at clinical onset.

BACKGROUND: No data are available on the occurrence of gray matter lesions (GML) in the cerebellum of pediatric multiple sclerosis (pedMS). OBJECTIVES: We analyzed frequency, number and topography of GML, and their correlation with cerebellar-related disability in pedMS at clinical onset. METHODS: Fifteen adolescents with pedMS (12F/3M; mean age 14.9 ± 2.2, range 11-17) were studied. Neurological and cognitive evaluations were done by means of EDSS, Trail Making Test-Part B (TMT-B) and Symbol Digit Modalities Test-oral version (SDMT). Cerebellar GML were investigated with double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) sequences obtained with a 3 T-MRI scan. RESULTS: All patients had white matter lesions (WML) and/or GML in the cerebellum. A significantly higher GML number was observed on PSIR compared to DIR (mean 2.3 ± 2.3 vs 1.1 ± 1.6; median 2.0 (IQR 1.0-2.0) vs 1.0 (IQR 0.0-1.5); p = 0.004). GML were observed in 14/15 (93.3%) patients and were more frequent in the posterior than in the anterior lobe (mean 1.8 ± 2.2 vs 0.47 ± 0.74; median 2.0 (IQR 0.5-2.0) vs 0.0 (IQR 0.0-1.0); p = 0.044). No correlation was found between lesion number or topography and EDSS (r = 0.12, p = 0.69), TMT-B and SDMT. CONCLUSION: At clinical onset, cerebellar GML are common in pedMS, are very often asymptomatic, do not correlate with physical and cognitive disability, and more frequently affect the posterior lobe.

Enlarged Virchow Robin spaces associate with cognitive decline in multiple sclerosis.

The clinical significance of Virchow Robin spaces (VRS) in inflammatory brain disorders, especially in multiple sclerosis (MS), is still undefined. We analysed enlarged VRS (eVRS) by means of phase sensitive inversion recovery (PSIR) MRI sequence and investigated their association with inflammation or brain atrophy, and to clinical or physical disability. Forty-three MS patients (21 clinically isolated syndrome suggestive of MS [CIS], 15 RRMS, 7 progressive [PMS]) and 10 healthy controls (HC) were studied. 3DT1, 3DFLAIR and 2DPSIR images were obtained with a 3T MRI scanner. eVRS number and volume were calculated by manual segmentation (ITK-SNAP). Freesurfer was used to assess brain parenchymal fraction (BPF). All patients underwent clinical (EDSS) and cognitive (Rao's BRB and DKEFS) evaluation. eVRS number and volume resulted significantly higher on 2D-PSIR compared to both 3D-T1 (p<0.001) and 3D-FLAIR (p<0.001) and were significantly increased in CIS compared to HC (p<0.05), in PMS and RRMS compared to CIS (p<0.001) and in male versus female patients (p<0.05). eVRS volume increased significantly with disease duration (r = 0.6) but did not correlate with EDSS. eVRS significantly correlated with SPARTd (r = -0.47) and DKEFSfs (r = -0.46), especially when RRMS and PMS were merged in a single group (r = 0.89, p = 0.002 and r = 0.66, p = 0.009 respectively), while no correlation was found with BPF (r = 0.3), gadolinium-enhancing lesions (r = 0.2) and WMT2 lesion volume (r = 0.2). 2DPSIR allowed the detection of an impressive higher number of eVRS compared to 3DT1 and 3DFLAIR. eVRS associate with SPARTd and DKEFSfs failure in relapse-onset MS, suggesting they may contribute to cognitive decline in MS.