Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection.

As severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections have been shown to affect the central nervous system, the investigation of associated alterations of brain structure and neuropsychological sequelae is crucial to help address future health care needs. Therefore, we performed a comprehensive neuroimaging and neuropsychological assessment of 223 nonvaccinated individuals recovered from a mild to moderate SARS-CoV-2 infection (100 female/123 male, age [years], mean ± SD, 55.54 ± 7.07; median 9.7 mo after infection) in comparison with 223 matched controls (93 female/130 male, 55.74 ± 6.60) within the framework of the Hamburg City Health Study. Primary study outcomes were advanced diffusion MRI measures of white matter microstructure, cortical thickness, white matter hyperintensity load, and neuropsychological test scores. Among all 11 MRI markers tested, significant differences were found in global measures of mean diffusivity (MD) and extracellular free water which were elevated in the white matter of post-SARS-CoV-2 individuals compared to matched controls (free water: 0.148 ± 0.018 vs. 0.142 ± 0.017, P < 0.001; MD [10-3 mm2/s]: 0.747 ± 0.021 vs. 0.740 ± 0.020, P < 0.001). Group classification accuracy based on diffusion imaging markers was up to 80%. Neuropsychological test scores did not significantly differ between groups. Collectively, our findings suggest that subtle changes in white matter extracellular water content last beyond the acute infection with SARS-CoV-2. However, in our sample, a mild to moderate SARS-CoV-2 infection was not associated with neuropsychological deficits, significant changes in cortical structure, or vascular lesions several months after recovery. External validation of our findings and longitudinal follow-up investigations are needed.

Fixel-Based Analysis Reveals Tau-Related White Matter Changes in Early Stages of Alzheimer's Disease.

Several studies have shown white matter (WM) abnormalities in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aß-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aß-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics.

Excessive interstitial free-water in cortical gray matter preceding accelerated volume changes in individuals at clinical high risk for psychosis.

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.

Brain morphometry in former American football players: findings from the DIAGNOSE CTE research project.

Exposure to repetitive head impacts in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE), which currently can be diagnosed only at post-mortem. American football players are at higher risk of developing CTE given their exposure to repetitive head impacts. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at post-mortem in living individuals using structural MRI. MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 54, age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each traumatic encephalopathy syndrome (TES) diagnosis, core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula, temporal pole and superior frontal gyrus. Post hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus, amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe Age × Group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggested that MRI morphometrics detect abnormalities in individuals with a history of repetitive head impact exposure that resemble the anatomic distribution of pathological findings from post-mortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggested that brain morphometry must be complemented by other types of measures to characterize individuals with repetitive head impacts.

Cortical microstructure and hemispheric specialization-A diffusion-imaging analysis in younger and older adults.

Characterizing cortical plasticity becomes increasingly important for identifying compensatory mechanisms and structural reserve in the ageing population. While cortical thickness (CT) largely contributed to systems neuroscience, it incompletely informs about the underlying neuroplastic pathophysiology. In turn, microstructural characteristics may correspond to atrophy mechanisms in a more sensitive way. Fractional anisotropy, a diffusion tensor imaging (DTI) measure, is inversely related to cortical histologic complexity. Axial diffusivity and radial diffusivity are assumed to be linked to the density of structures oriented perpendicular and parallel to the cortical surface, respectively. We hypothesized (1) that cortical DTI will reveal microstructural correlates for hemispheric specialization, particularly in the language and motor systems, and (2) that lateralization of cortical DTI parameters will show an age effect, paralleling age-related changes in activation, especially in the prefrontal cortex. We analysed data from healthy younger and older adult participants (N = 91). DTI and CT data were extracted from regions of the Destrieux atlas. Diffusion measures showed lateralization in specialized motor, language, visual, auditory and inferior parietal cortices. Age-dependent increased lateralization for DTI measures was observed in the prefrontal, angular, superior temporal and lateral occipital cortex. CT did not show any age-dependent alterations in lateralization. Our observations argue that cortical DTI can capture microstructural properties associated with functional specialization, resembling findings from histology. Age effects on diffusion measures in the integrative prefrontal and parietal areas may shed novel light on the atrophy-related plasticity in healthy ageing.

Characterization of the extracellular free water signal in schizophrenia using multi-site diffusion MRI harmonization.

Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders at different illness stages and ages (15-58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. In individuals with schizophrenia, average whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years (effect size range = [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years, an attenuated monotonic increase in FW was observed, but with markedly smaller effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p = 0.006), independent of the effects of other clinical and demographic data. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings provide further evidence that elevations in the FW are present in individuals with schizophrenia, with the greatest differences in the FW being observed in those at the early stages of the disorder, which might suggest acute extracellular processes.

Neurological soft signs in adolescents are associated with brain structure.

Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13-16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS- group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS- group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation.

A preliminary choroid plexus volumetric study in individuals with psychosis.

The choroid plexus (ChP) is part of the blood-cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging-based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.

Shared and distinct white matter abnormalities in adolescent-onset schizophrenia and adolescent-onset psychotic bipolar disorder.

BACKGROUND: While adolescent-onset schizophrenia (ADO-SCZ) and adolescent-onset bipolar disorder with psychosis (psychotic ADO-BPD) present a more severe clinical course than their adult forms, their pathophysiology is poorly understood. Here, we study potentially state- and trait-related white matter diffusion-weighted magnetic resonance imaging (dMRI) abnormalities along the adolescent-onset psychosis continuum to address this need. METHODS: Forty-eight individuals with ADO-SCZ (20 female/28 male), 15 individuals with psychotic ADO-BPD (7 female/8 male), and 35 healthy controls (HCs, 18 female/17 male) underwent dMRI and clinical assessments. Maps of extracellular free-water (FW) and fractional anisotropy of cellular tissue (FAT) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FAT and FW values were extracted, averaged across all voxels that demonstrated group differences, and then utilized to test for the influence of age, medication, age of onset, duration of illness, symptom severity, and intelligence. RESULTS: Individuals with adolescent-onset psychosis exhibited pronounced FW and FAT abnormalities compared to HCs. FAT reductions were spatially more widespread in ADO-SCZ. FW increases, however, were only present in psychotic ADO-BPD. In HCs, but not in individuals with adolescent-onset psychosis, FAT was positively related to age. CONCLUSIONS: We observe evidence for cellular (FAT) and extracellular (FW) white matter abnormalities in adolescent-onset psychosis. Although cellular white matter abnormalities were more prominent in ADO-SCZ, such alterations may reflect a shared trait, i.e. neurodevelopmental pathology, present across the psychosis spectrum. Extracellular abnormalities were evident in psychotic ADO-BPD, potentially indicating a more dynamic, state-dependent brain reaction to psychosis.

Mapping acute neuroinflammation in vivo with diffusion-MRI in rats given a systemic lipopolysaccharide challenge.

It is becoming increasingly apparent that neuroinflammation plays a critical role in an array of neurological and psychiatric disorders. Recent studies have demonstrated the potential of diffusion MRI (dMRI) to characterize changes in microglial density and morphology associated with neuroinflammation, but these were conducted mostly ex vivo and/or in extreme, non-physiological animal models. Here, we build upon these studies by investigating the utility of well-established dMRI methods to detect neuroinflammation in vivo in a more clinically relevant animal model of sickness behavior. We show that diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) indicate widespread increases in diffusivity in the brains of rats given a systemic lipopolysaccharide challenge (n = 20) vs. vehicle-treated controls (n = 12). These diffusivity changes correlated with histologically measured changes in microglial morphology, confirming the sensitivity of dMRI to neuroinflammatory processes. This study marks a further step towards establishing a noninvasive indicator of neuroinflammation, which would greatly facilitate early diagnosis and treatment monitoring in various neurological and psychiatric diseases.

Cognitive deficits, clinical variables, and white matter microstructure in schizophrenia: a multisite harmonization study.

Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).

Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.

Free water corrected diffusion tensor imaging discriminates between good and poor outcomes of comatose patients after cardiac arrest.

OBJECTIVES: Approximately 50% of comatose patients after cardiac arrest never regain consciousness. Cerebral ischaemia may lead to cytotoxic and/or vasogenic oedema, which can be detected by diffusion tensor imaging (DTI). Here, we evaluate the potential value of free water corrected mean diffusivity (MD) and fractional anisotropy (FA) based on DTI, for the prediction of neurological recovery of comatose patients after cardiac arrest. METHODS: A total of 50 patients after cardiac arrest were included in this prospective cohort study in two Dutch hospitals. DTI was obtained 2-4 days after cardiac arrest. Outcome was assessed at 6 months, dichotomised as poor (cerebral performance category 3-5; n = 20) or good (n = 30) neurological outcome. We calculated the whole brain mean MD and FA and compared between patients with good and poor outcomes. In addition, we compared a preliminary prediction model based on clinical parameters with or without the addition of MD and FA. RESULTS: We found significant differences between patients with good and poor outcome of mean MD (good: 726 [702-740] × 10-6 mm2/s vs. poor: 663 [575-736] × 10-6 mm2/s; p = 0.01) and mean FA (0.30 ± 0.03 vs. 0.28 ± 0.03; p = 0.03). An exploratory prediction model combining clinical parameters, MD and FA increased the sensitivity for reliable prediction of poor outcome from 60 to 85%, compared to the model containing clinical parameters only, but confidence intervals are overlapping. CONCLUSIONS: Free water-corrected MD and FA discriminate between patients with good and poor outcomes after cardiac arrest and hold the potential to add to multimodal outcome prediction. KEY POINTS: • Whole brain mean MD and FA differ between patients with good and poor outcome after cardiac arrest. • Free water-corrected MD can better discriminate between patients with good and poor outcome than uncorrected MD. • A combination of free water-corrected MD (sensitive to grey matter abnormalities) and FA (sensitive to white matter abnormalities) holds potential to add to the prediction of outcome.

The fornix supports episodic memory during childhood.

Episodic memory relies on the coordination of widespread brain regions that reconstruct spatiotemporal details of an episode. These topologically dispersed brain regions can rapidly communicate through structural pathways. Research in animal and human lesion studies implicate the fornix-the major output pathway of the hippocampus-in supporting various aspects of episodic memory. Because episodic memory undergoes marked changes in early childhood, we tested the link between the fornix and episodic memory in an age window of robust memory development (ages 4-8 years). Children were tested on the stories subtest from the Children's Memory Scale, a temporal order memory task, and a source memory task. Fornix streamlines were reconstructed using probabilistic tractography to estimate fornix microstructure. In addition, we measured fornix macrostructure and computed free water. To assess selectivity of our findings, we also reconstructed the uncinate fasciculus. Findings show that children's memory increases from ages 4 to 8 and that fornix micro- and macrostructure increases between ages 4 and 8. Children's memory performance across nearly every memory task correlated with individual differences in fornix, but not uncinate fasciculus, white matter. These findings suggest that the fornix plays an important role in supporting the development of episodic memory, and potentially semantic memory, in early childhood.

Free water diffusion MRI and executive function with a speed component in healthy aging.

Extracellular free water (FW) increases are suggested to better provide pathophysiological information in brain aging than conventional biomarkers such as fractional anisotropy. The aim of the present study was to determine the relationship between conventional biomarkers, FW in white matter hyperintensities (WMH), FW in normal appearing white matter (NAWM) and in white matter tracts and executive functions (EF) with a speed component in elderly persons. We examined 226 healthy elderly participants (median age 69.83 years, IQR: 56.99-74.42) who underwent brain MRI and neuropsychological examination. FW in WMH and in NAWM as well as FW corrected diffusion metrics and measures derived from conventional MRI (white matter hyperintensities, brain volume, lacunes) were used in partial correlation (adjusted for age) to assess their correlation with EF with a speed component. Random forest analysis was used to assess the relative importance of these variables as determinants. Lastly, linear regression analyses of FW in white matter tracts corrected for risk factors of cognitive and white matter deterioration, were used to examine the role of specific tracts on EF with a speed component, which were then ranked with random forest regression. Partial correlation analyses revealed that almost all imaging metrics showed a significant association with EF with a speed component (r = -0.213 - 0.266). Random forest regression highlighted FW in WMH and in NAWM as most important among all diffusion and structural MRI metrics. The fornix (R2=0.421, p = 0.018) and the corpus callosum (genu (R2 = 0.418, p = 0.021), prefrontal (R2 = 0.416, p = 0.026), premotor (R2 = 0.418, p = 0.021)) were associated with EF with a speed component in tract based regression analyses and had highest variables importance. In a normal aging population FW in WMH and NAWM is more closely related to EF with a speed component than standard DTI and brain structural measures. Higher amounts of FW in the fornix and the frontal part of the corpus callosum leads to deteriorating EF with a speed component.

Cross-site harmonization of multi-shell diffusion MRI measures based on rotational invariant spherical harmonics (RISH).

Quantification methods based on the acquisition of diffusion magnetic resonance imaging (dMRI) with multiple diffusion weightings (e.g., multi-shell) are becoming increasingly applied to study the in-vivo brain. Compared to single-shell data for diffusion tensor imaging (DTI), multi-shell data allows to apply more complex models such as diffusion kurtosis imaging (DKI), which attempts to capture both diffusion hindrance and restriction effects, or biophysical models such as NODDI, which attempt to increase specificity by separating biophysical components. Because of the strong dependence of the dMRI signal on the measurement hardware, DKI and NODDI metrics show scanner and site differences, much like other dMRI metrics. These effects limit the implementation of multi-shell approaches in multicenter studies, which are needed to collect large sample sizes for robust analyses. Recently, a post-processing technique based on rotation invariant spherical harmonics (RISH) features was introduced to mitigate cross-scanner differences in DTI metrics. Unlike statistical harmonization methods, which require repeated application to every dMRI metric of choice, RISH harmonization is applied once on the raw data, and can be followed by any analysis. RISH features harmonization has been tested on DTI features but not its generalizability to harmonize multi-shell dMRI. In this work, we investigated whether performing the RISH features harmonization of multi-shell dMRI data removes cross-site differences in DKI and NODDI metrics while retaining longitudinal effects. To this end, 46 subjects underwent a longitudinal (up to 3 time points) two-shell dMRI protocol at 3 imaging sites. DKI and NODDI metrics were derived before and after harmonization and compared both at the whole brain level and at the voxel level. Then, the harmonization effects on cross-sectional and on longitudinal group differences were evaluated. RISH features averaged for each of the 3 sites exhibited prominent between-site differences in the frontal and posterior part of the brain. Statistically significant differences in fractional anisotropy, mean diffusivity and mean kurtosis were observed both at the whole brain and voxel level between all the acquisition sites before harmonization, but not after. The RISH method also proved effective to harmonize NODDI metrics, particularly in white matter. The RISH based harmonization maintained the magnitude and variance of longitudinal changes as compared to the non-harmonized data of all considered metrics. In conclusion, the application of RISH feature based harmonization to multi-shell dMRI data can be used to remove cross-site differences in DKI metrics and NODDI analyses, while retaining inherent relations between longitudinal acquisitions.

Superficial white matter microstructure affects processing speed in cerebral small vessel disease.

White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD), which contributes to about 50% of dementias worldwide. Microstructural alterations in deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In 141 CSVD patients, processing speed was assessed using Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (volume on T2-FLAIR) and diffusion MRI measures. SWM imaging measures had a large contribution to processing speed, despite a relatively low SWM WMH burden. Across all imaging measures, SWM free water (FW) had the strongest association with processing speed, followed by SWM mean diffusivity (MD). SWM FW was the only marker to significantly increase between two subgroups with the lowest WMH burdens. When comparing two subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Mediation analysis revealed that SWM FW fully mediated the association between WMH volume and processing speed, while no mediation effect of MD or DWM FW was observed. Overall, results suggest that the SWM has an important contribution to processing speed, while SWM FW is a sensitive imaging marker associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes.

Brain white matter extracellular free-water increases are related to reduced neurocognitive function in systemic lupus erythematosus.

OBJECTIVES: Brain white matter (WM) microstructural changes evaluated by diffusion MRI are well documented in patients with SLE. Yet, the conventional diffusion tensor imaging technique fails to differentiate WM changes that originate from tissue alterations from those due to increased extracellular free water (FW) related to neuroinflammation, microvascular disruption, atrophy, or other extracellular processes. Here, we sought to delineate changes in WM tissue microstructure and extracellular FW volume and examine their relationships with neurocognitive function in SLE patients. METHODS: Twenty SLE patients [16 females, aged 36.0 (10.6)] without clinically overt neuropsychiatric manifestation and 61 healthy controls (HCs) [29 females, aged 29.2 (9.4)] underwent diffusion MRI and computerized neuropsychological assessments cross-sectionally. The FW imaging method was applied to compare microstructural tissue changes and extracellular FW volume of the brain WM between SLE patients and HCs. Association between extracellular FW changes and neurocognitive performance was studied. RESULTS: SLE patients had higher WM extracellular FW compared with HCs (family-wise-error-corrected P < 0.05), while no group difference was found in FW-corrected tissue compartment and structural connectivity metrics. Extracellular FW increases in SLE patients were associated with poorer neurocognitive performance that probed sustained attention (P = 0.022) and higher cumulative glucocorticoid dose (P = 0.0041). Such findings remained robust after controlling for age, gender, intelligence quotient, and total WM volume. CONCLUSION: The association between WM extracellular FW increases and reduced neurocognitive performance suggest possible microvascular degradation and/or neuroinflammation in SLE patients with clinically inactive disease. The mechanistic impact of cumulative glucocorticoids on WM FW deserves further evaluation.

Thalamic Dorsomedial Nucleus Free Water Correlates with Cognitive Decline in Parkinson's Disease.

BACKGROUND: Brain diffusion tensor imaging (DTI) has been shown to reflect cognitive changes in early Parkinson's disease (PD) but the diffusion-based measure free water (FW) has not been previously assessed. OBJECTIVES: To assess if FW in the thalamic nuclei primarily involved with cognition (ie, the dorsomedial [DMN] and anterior [AN] nuclei), the nucleus basalis of Meynert (nbM), and the hippocampus correlates with and is associated with longitudinal cognitive decline and distinguishes cognitive status at baseline in early PD. Also, to explore how FW compares with conventional DTI, FW-corrected DTI, and volumetric assessments for these outcomes. METHODS: Imaging data and Montreal Cognitive Assessment (MoCA) scores from the Parkinson's Progression Markers Initiative database were analyzed using partial correlations and ANCOVA. Primary outcome multiple comparisons were corrected for false discovery rate (q value). RESULTS: Thalamic DMN FW changes over 1 year correlated with MoCA changes over both 1 and 3 years (partial correlations -0.222, q = 0.040, n = 130; and - 0.229, q = 0.040, n = 123, respectively; mean PD duration at baseline = 6.85 months). NbM FW changes over 1 year only correlated with MoCA changes over 3 years (-0.222, q = 0.040). Baseline hippocampal FW was associated with cognitive impairment at 3 years (q = 0.040) and baseline nbM FW distinguished PD-normal cognition (MoCA ≥26) from PD-cognitive impairment (MoCA ≤25), (q = 0.008). The exploratory comparisons showed FW to be the most robust assessment modality for all outcomes. CONCLUSIONS: Thalamic DMN FW is a promising cognition progression biomarker in early PD that may assist in identifying cognition protective therapies in clinical trials. FW is a robust assessment modality for these outcomes. © 2021 International Parkinson and Movement Disorder Society.

Diffusion Magnetic Resonance Imaging Detects Progression in Parkinson's Disease: A Placebo-Controlled Trial of Rasagiline.

BACKGROUND: Rasagiline has received attention as a potential disease-modifying therapy for Parkinson's disease (PD). Whether rasagiline is disease modifying remains in question. OBJECTIVE: The main objective of this study was to determine whether rasagiline has disease-modifying effects in PD over 1 year. Secondarily we evaluated two diffusion magnetic resonance imaging pulse sequences to determine the best sequence to measure disease progression. METHODS: This prospective, randomized, double-blind, placebo-controlled trial assessed the effects of rasagiline administered at 1 mg/day over 12 months in early-stage PD. The primary outcome was 1-year change in free-water accumulation in posterior substantia nigra (pSN) measured using two diffusion magnetic resonance imaging pulse sequences, one with a repetition time (TR) of 2500 ms (short TR; n = 90) and one with a TR of 6400 ms (long TR; n = 75). Secondary clinical outcomes also were assessed. RESULTS: Absolute change in pSN free-water accumulation was not significantly different between groups (short TR: P = 0.346; long TR: P = 0.228). No significant differences were found in any secondary clinical outcomes between groups. Long TR, but not short TR, data show pSN free-water increased significantly over 1 year (P = 0.025). Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III increased significantly over 1 year (P = 0.009), and baseline free-water in the pSN correlated with the 1-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III (P = 0.004) and 1-year change in bradykinesia score (P = 0.044). CONCLUSIONS: We found no evidence that 1 mg/day rasagiline has a disease-modifying effect in PD over 1 year. We found pSN free-water increased over 1 year, and baseline free-water relates to clinical motor progression, demonstrating the importance of diffusion imaging parameters for detecting and predicting PD progression. © 2021 International Parkinson and Movement Disorder Society.