Cerebellar connectome alterations and associated genetic signatures in multiple sclerosis and neuromyelitis optica spectrum disorder.

BACKGROUND: The cerebellum plays key roles in the pathology of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but the way in which these conditions affect how the cerebellum communicates with the rest of the brain (its connectome) and associated genetic correlates remains largely unknown. METHODS: Combining multimodal MRI data from 208 MS patients, 200 NMOSD patients and 228 healthy controls and brain-wide transcriptional data, this study characterized convergent and divergent alterations in within-cerebellar and cerebello-cerebral morphological and functional connectivity in MS and NMOSD, and further explored the association between the connectivity alterations and gene expression profiles. RESULTS: Despite numerous common alterations in the two conditions, diagnosis-specific increases in cerebellar morphological connectivity were found in MS within the cerebellar secondary motor module, and in NMOSD between cerebellar primary motor module and cerebral motor- and sensory-related areas. Both diseases also exhibited decreased functional connectivity between cerebellar motor modules and cerebral association cortices with MS-specific decreases within cerebellar secondary motor module and NMOSD-specific decreases between cerebellar motor modules and cerebral limbic and default-mode regions. Transcriptional data explained > 37.5% variance of the cerebellar functional alterations in MS with the most correlated genes enriched in signaling and ion transport-related processes and preferentially located in excitatory and inhibitory neurons. For NMOSD, similar results were found but with the most correlated genes also preferentially located in astrocytes and microglia. Finally, we showed that cerebellar connectivity can help distinguish the three groups from each other with morphological connectivity as predominant features for differentiating the patients from controls while functional connectivity for discriminating the two diseases. CONCLUSIONS: We demonstrate convergent and divergent cerebellar connectome alterations and associated transcriptomic signatures between MS and NMOSD, providing insight into shared and unique neurobiological mechanisms underlying these two diseases.

Structural and functional hippocampal alterations in Multiple sclerosis and neuromyelitis optica spectrum disorder.

BACKGROUND: Hippocampal involvement may differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: To investigate the morphometric, diffusion and functional alterations in hippocampus in MS and NMOSD and the clinical significance. METHODS: A total of 752 participants including 236 MS, 236 NMOSD and 280 healthy controls (HC) were included in this retrospective multi-center study. The hippocampus and subfield volumes, fractional anisotropy (FA) and mean diffusivity (MD), amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and their associations with clinical variables were investigated. RESULTS: The hippocampus showed significantly lower volume, FA and greater MD in MS compared to NMOSD and HC (p < 0.05), while no abnormal ALFF or DC was identified in any group. Hippocampal subfields were affected in both diseases, though subiculum, presubiculum and fimbria showed significantly lower volume only in MS (p < 0.05). Significant correlations between diffusion alterations, several subfield volumes and clinical variables were observed in both diseases, especially in MS (R = -0.444 to 0.498, p < 0.05). FA and MD showed fair discriminative power between MS and HC, NMOSD and HC (AUC > 0.7). CONCLUSIONS: Hippocampal atrophy and diffusion abnormalities were identified in MS and NMOSD, partly explaining how clinical disability and cognitive impairment are differentially affected.

Subtyping relapsing-remitting multiple sclerosis using structural MRI.

BACKGROUND AND PURPOSE: Subtyping relapsing-remitting multiple sclerosis (RRMS) patients may help predict disease progression and triage patients for treatment. We aimed to subtype RRMS patients by structural MRI and investigate their clinical significances. METHODS: 155 relapse-remitting MS (RRMS) and 210 healthy controls (HC) were retrospectively enrolled with structural 3DT1, diffusion tensor imaging (DTI) and resting-state functional MRI. Z scores of cortical and deep gray matter volumes (CGMV and DGMV) and white matter fractional anisotropy (WM-FA) in RRMS patients were calculated based on means and standard deviations of HC. We defined RRMS as "normal" (- 2 < z scores of both GMV and WM-FA), DGM (z scores of DGMV < - 2), and DGM-plus types (z scores of DGMV and [CGMV or WM-FA] < - 2) according to combinations of z scores compared to HC. Expanded disability status scale (EDSS), cognitive and functional MRI measurements, and conversion rate to secondary progressive MS (SPMS) at 5-year follow-up were compared between subtypes. RESULTS: 77 (49.7%) patients were "normal" type, 37 (23.9%) patients were DGM type and 34 (21.9%) patients were DGM-plus type. 7 (4.5%) patients who were not categorized into the above types were excluded. DGM-plus type had the highest EDSS. Both DGM and DGM-plus types had more severe cognitive impairment than "normal" type. Only DGM-plus type showed decreased functional MRI measures compared to HC. A higher conversion ratio to SPMS in DGM-plus type (55%) was identified compared to "normal" type (14%, p < 0.001) and DGM type (20%, p = 0.005). CONCLUSION: Three MRI-subtypes of RRMS were identified with distinct clinical and imaging features and different prognosis.

Brain structural and functional alterations in MOG antibody disease.

BACKGROUND: The impact of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) on brain structure and function is unknown. OBJECTIVES: The aim of this study was to study the multimodal brain MRI alterations in MOGAD and to investigate their clinical significance. METHODS: A total of 17 MOGAD, 20 aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4 + NMOSD), and 28 healthy controls (HC) were prospectively recruited. Voxel-wise gray matter (GM) volume, fractional anisotropy (FA), mean diffusivity (MD), and degree centrality (DC) were compared between groups. Clinical associations and differential diagnosis were determined using partial correlation and stepwise logistic regression. RESULTS: In comparison with HC, MOGAD had GM atrophy in frontal and temporal lobe, insula, thalamus, and hippocampus, and WM fiber disruption in optic radiation and anterior/posterior corona radiata; DC decreased in cerebellum and increased in temporal lobe. Compared to AQP4 + NMOSD, MOGAD presented lower GM volume in postcentral gyrus and decreased DC in cerebellum. Hippocampus/parahippocampus atrophy associated with Expanded Disability Status Scale (R = -0.55, p = 0.04) and California Verbal Learning Test (R = 0.62, p = 0.031). The differentiation of MOGAD from AQP4 + NMOSD achieved an accuracy of 95% using FA in splenium of corpus callosum and DC in occipital gyrus. CONCLUSION: Distinct structural and functional alterations were identified in MOGAD. Hippocampus/parahippocampus atrophy associated with clinical disability and cognitive impairment.

Volumetric reduction of cerebellar lobules associated with memory decline across the adult lifespan.

BACKGROUND: The human cerebellum plays an essential role in motor control, is involved in cognitive function and helps to regulate emotional responses. However, little is known about the relationship between cerebellar lobules and age-related memory decline. We aimed to investigate volume alterations in cerebellar lobules at different ages and assess their correlations with reduced memory recall abilities. METHODS: A sample of 275 individuals were divided into the following four groups: 20-35 years (young), 36-50 years (early-middle age), 51-65 years (late-middle age), and 66-89 years (old). Volumes of the cerebellar lobules were obtained using volBrain software. Analysis of covariance and post hoc analysis were used to analyze group differences in cerebellar lobular volumes, and multiple comparisons were performed using the Bonferroni method. Spearman correlation was used to investigate the relationship between lobular volumes and memory recall scores. RESULTS: In this study, we found that older adults had smaller cerebellar volumes than the other subjects. Volumetric decreases in size were noted in bilateral lobule VI and lobule crus I. Moreover, the volumes of bilateral lobule crus I, lobule VI, and right lobule IV were significantly associated with memory recall scores. CONCLUSIONS: In the present study, we found that some lobules of the cerebellum appear more predisposed to age-related changes than other lobules. These findings provide further evidence that specific regions of the cerebellum could be used to assess the risk of memory decline across the adult lifespan.

Study on the sub-regions volume of hippocampus and amygdala in schizophrenia.

BACKGROUND: Many studies have found volume changes in the hippocampus and amygdala in patients with schizophrenia, but these findings have not reached an agreement. Particularly, few results showed the volumes of the sub-regions of the amygdala. In this research, we aim to clarify volume changes of hippocampus and amygdala sub-regions in patients with schizophrenia. METHODS: The sample consisted of 69 patients with schizophrenia and 72 control subjects aged from 18 to 65 years. FreeSurfer 6.0 software was used on T1-weighted images to assess the volumes of hippocampus and amygdala and their sub-regions. The general linear model (GLM) was used to analyze the volume changes between the two groups. False discovery rate (FDR) correction was performed, and the significance level was set at 0.05. RESULTS: The hippocampus volume in schizophrenia showed reduction compared to healthy control (P<0.05). Several hippocampal subfields showed smaller volume in schizophrenia patients, including bilateral presubiculum and molecular layer, left hippocampal tail, subiculum and cornus ammonis (CA)1, and right parasubiculum (P<0.05). Left amygdala volume showed a decrease as well, sub-regions including the bilateral basal nucleus, anterior-amygdaloid-area (AAA), paralaminar nucleus and left lateral nucleus (P<0.05). CONCLUSIONS: Several sub-regions of hippocampus and amygdala showed a volumetric decline in patients group, which suggest the key roles of these regions in the pathophysiology of schizophrenia. Based on these results, we speculate that these regions could be used to assess the early finding of schizophrenia.

Characterizing mechanical and medical imaging properties of polyvinyl chloride-based tissue-mimicking materials.

Polyvinyl chloride (PVC) is a commonly used tissue-mimicking material (TMM) for phantom construction using 3D printing technology. PVC-based TMMs consist of a mixture of PVC powder and dioctyl terephthalate as a softener. In order to allow the clinical use of a PVC-based phantom use across CT and magnetic resonance imaging (MRI) imaging platforms, we evaluated the mechanical and physical imaging characteristics of ten PVC samples. The samples were made with different PVC-softener ratios to optimize phantom bioequivalence with physiologic human tissue. Phantom imaging characteristics, including computed tomography (CT) number, MRI relaxation time, and mechanical properties (e.g., Poisson's ratio and elastic modulus) were quantified. CT number varied over a range of approximately -10 to 110 HU. The relaxation times of the T1-weighted and T2-weighted images were 206.81 ± 17.50 and 20.22 ± 5.74 ms, respectively. Tensile testing was performed to evaluate mechanical properties on the three PVC samples that were closest to human tissue. The elastic moduli for these samples ranged 7.000-12.376 MPa, and Poisson's ratios were 0.604-0.644. After physical and imaging characterization of the various PVC-based phantoms, we successfully produced a bioequivalent phantom compatible with multimodal imaging platforms for machine calibration and image optimization/benchmarking. By combining PVC with 3D printing technologies, it is possible to construct imaging phantoms simulating human anatomies with tissue equivalency.

3D-printed breast phantom for multi-purpose and multi-modality imaging.

BACKGROUND: Breast imaging technology plays an important role in breast cancer planning and treatment. Recently, three-dimensional (3D) printing technology has become a trending issue in phantom constructions for medical applications, with its advantages of being customizable and cost-efficient. However, there is no current practice in the field of multi-purpose breast phantom for quality control (QC) in multi-modalities imaging. The purpose of this study was to fabricate a multi-purpose breast phantom with tissue-equivalent materials via a 3D printing technique for QC in multi-modalities imaging. METHODS: We used polyvinyl chloride (PVC) based materials and a 3D printing technique to construct a breast phantom. The phantom incorporates structures imaged in the female breast such as microcalcifications, fiber lesions, and tumors with different sizes. Moreover, the phantom was used to assess the sensitivity of lesion detection, depth resolution, and detectability thresholds with different imaging modalities. Phantom tissue equivalent properties were determined using computed tomography (CT) attenuation [Hounsfield unit (HU)] and magnetic resonance imaging (MRI) relaxation times. RESULTS: The 3D-printed breast phantom had an average background value of 36.2 HU, which is close to that of glandular breast tissue (40 HU). T1 and T2 relaxation times had an average relaxation time of 206.81±17.50 and 20.22±5.74 ms, respectively. Mammographic imaging had improved detection of microcalcification compared with ultrasound and MRI with multiple sequences [T1WI, T2WI and short inversion time inversion recovery (STIR)]. Soft-tissue lesion detection and cylindrical tumor contrast were superior with mammography and MRI compared to ultrasound. Hemispherical tumor detection was similar regardless of the imaging modality used. CONCLUSIONS: We developed a multi-purpose breast phantom using a 3D printing technique and determined its value for multi-modal breast imaging studies.

Age-related changes in cortical and subcortical structures of healthy adult brains: A surface-based morphometry study.

BACKGROUND: Cerebral structures in both cortical and subcortical regions change with aging. More specific and comprehensive studies are needed to better elucidate these changes. PURPOSE: To investigate the relationships between age and cerebral structures regarding cortical and subcortical changes. STUDY TYPE: Cross-cohort research. POPULATION: 54 healthy adults (28 females) aged 21-71 years. FIELD STRENGTH/SEQUENCE: T1 -weighted imaging was performed at 1.5T. ASSESSMENT: The cortical thickness, local gyrification index (LGI), and the volumes of total gray matter (GM), white matter (WM), white matter hyperintensity (WMH), deep gray matter nuclei (putamen, pallidum, thalamus, caudate, amygdala, accumbens area, and hippocampus), ventricles, and hippocampal subfields were obtained using FreeSurfer software. STATISTICAL TESTS: Regression analysis was performed to determine the relationships between age and cortical thickness, LGI, and volumes of subcortical structures. Uncorrected P values ≤ 0.001 and R2 > 0.16 were considered significant. RESULTS: The cortical thickness and LGI decreased with age throughout almost all brain regions (R2 > 0.16; P ≤ 0.001). Except for the volumes of the WM and 4th ventricle (R2 < 0.16; P > 0.001), the volumes of the GM, WMH, lateral ventricle, inferior lateral ventricle, and 3rd ventricle showed a nonlinear correlation with aging (R2 > 0.16; P ≤ 0.001). For deep gray matter nuclei, the thalamus volume was significantly decreased with aging (R2 = 0.256; P = 0.001). Additionally, the hippocampus volume was initially increased and then decreased at age of 50, mainly in the granule cell layer of the dentate gyrus (GC-DG), cornus ammonis 2/3 (CA2/3), CA4, and fissure (R2 > 0.16; P ≤ 0.001). The volumes of the putamen, pallidum, accumbens area, amygdala and caudate showed no significance with aging (R2 < 0.16; P > 0.001). DATA CONCLUSION: The results comprehensively show the relationships between age and cerebral structures in multiple brain regions, and these findings may help identify normal aging and other age-related neuroradiological disorders. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:152-163.

The Volume of Hippocampal Subfields in Relation to Decline of Memory Recall Across the Adult Lifespan.

Background: The hippocampus is an important limbic structure closely related to memory function. However, few studies have focused on the association between hippocampal subfields and age-related memory decline. We investigated the volume alterations of hippocampal subfields at different ages and assessed the correlations with Immediate and Delayed recall abilities. Materials and Methods: A total of 275 participants aged 20-89 years were classified into 4 groups: Young, 20-35 years; Middle-early, 36-50 years; Middle-late, 51-65 years; Old, 66-89 years. All data were acquired from the Dallas Lifespan Brain Study (DLBS). The volumes of hippocampal subfields were obtained using Freesurfer software. Analysis of covariance (ANCOVA) was performed to analyze alterations of subfield volumes among the 4 groups, and multiple comparisons between groups were performed using the Bonferroni method. Spearman correlation with false discovery rate correction was used to investigate the relationship between memory recall scores and hippocampal subfield volumes. Results: Apart from no significant difference in the left parasubiculum (P = 0.269) and a slight difference in the right parasubiculum (P = 0.022), the volumes of other hippocampal subfields were significantly different across the adult lifespan (P < 0.001). The hippocampal fissure volume was increased in the Old group, while volumes for other subfields decreased. In addition, Immediate recall scores were associated with volumes of the bilateral molecular layer, granule cell layer of the dentate gyrus (GC-DG), cornus ammonis (CA) 1, CA2/3, CA4, left fimbria and hippocampal amygdala transition area (HATA), and right fissure (P < 0.05). Delayed recall scores were associated with the bilateral molecular layer, GC-DG, CA2/3 and CA4; left tail, presubiculum, CA1, subiculum, fimbria and HATA (P < 0.05). Conclusion: The parasubiculum volume was not significantly different across the adult lifespan, while atrophy in dementia patients in some studies. Based on these findings, we speculate that volume changes in this region might be considered as a biomarker for dementia disorders. Additionally, several hippocampal subfield volumes were significantly associated with memory scores, further highlighting the key role of the hippocampus in age-related memory decline. These regions could be used to assess the risk of memory decline across the adult lifespan.

Age-related changes in fiber tracts in healthy adult brains: A generalized q-sampling and connectometry study.

BACKGROUND: Generalized q-sampling (GQI) and connectometry analysis provide new indices, i.e., quantitative anisotropy (QA) and spin distribution function (SDF) in comparison with diffusion tensor imaging (DTI). They may provide more age-related changes in white matter (WM) in aging. PURPOSE: To investigate the feasibility of using GQI and connectometry analysis to determine WM properties changes in aging. STUDY TYPE: Cross-cohort research. POPULATION: Fifty normal adults (27 females) aged 21-71 years. FIELD STRENGTH/SEQUENCE: T1 -weighted images (T1 WI) and high angular resolution diffusion imaging (HARDI) images were acquired at 1.5T. ASSESSMENT: HARDI data were analyzed using DTI and GQI to obtain fractional anisotropy (FA), QA, fiber numbers, and fiber lengths for tract analysis and using q-space diffeomorphic reconstruction (QSDR) for the connectometry analysis. We compared differences of DTI, GQI, and connectometry analysis to reflect WM changes in aging. STATISTICAL TESTS: Associations between FA, QA, and fiber numbers and lengths and age were analyzed using Pearson's correlation coefficients. The connectometry analysis was conducted using a multiple linear regression analysis, including age and gender as factors. Uncorrected P-value/false discovery rate (FDR) (corrected for multiple comparisons) < 0.05 was considered statistically significant. RESULTS: More regional changes were detected in FA related to age than changes in QA (17 > 6 regions, P < 0.05). Fewer regional changes in fiber numbers and more changes of fiber lengths were observed for DTI than for GQI (5 < 8/10 > 7 regions, P < 0.05). However, DTI and GQI analyses revealed consistent results in some regions, including the genu of the corpus callosum (GCC), body of the corpus callosum (BCC), fornix (Fx), and anterior coronal radiation (ACR) (P < 0.05). The connectometry analysis showed more tract changes associated with age at an FDR of 0.05, which partially overlapped with the FA and QA. DATA CONCLUSION: GQI and connectometry provide more information about age-related tracts and complement the DTI findings. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2018;48:369-381.