Deep Gray Matter Atrophy Research Articles

Dynamics of choroid plexus volume is associated with the presence and development of fatigue in multiple sclerosis

BackgroundImmune-mediated processes are implicated in the pathogenesis of fatigue, a common symptom in multiple sclerosis (MS). The choroid plexus (CP) regulates central nervous system (CNS) immune homeostasis and undergoes volumetric...

Multimodal magnetic resonance longitudinal study on the deep gray matter in multiple sclerosis patients with teriflunomide

Disease-modifying therapies (DMTs) are used in an increasing number of patients with multiple sclerosis (MS). However, whether DMTs have intrinsic effects on deep gray matter (DGM) microstructure and atrophy is still poorly understood. In this study, we described the quantitative susceptibility values (QSV) and diffusion kurtosis imaging (DKI) metrics of DGM in relapsing–remitting MS (RRMS) patients and their association with cognitive deficits. We recruited 62 patients with RRMS receiving DMTs and 30 patients with RRMS not receiving DMTs underwent MRI on a 3T scanner. Fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), mean diffusivity (MD), mean kurtosis (MK), QSV and volumes of bilateral caudate nucleus (CAU), amygdala (AMYG), putamen (PUT), hippocampus (Hipp), globus pallidus (GP) and thalamus (THA) were measured. Correlation analysis was performed between those image indexes with longitudinal significant changes and clinical neurological scores, including Expanded Disability Status Scale (EDSS), Digit Span Testand (DST), Symbol Digit Modalities Test (SDMT), Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Significant longitudinal increases in FA, KFA and MK values were found in both groups in bilateral CAU, AMYG, PUT, Hipp, GP and THA (all p < 0.005). MD values of the right of CAU in the two groups were significant longitudinal increase (p = 0.009, p = 0.047); MD values of the right of GP (p = 0.042), the left of THA (p = 0.003), the right of THA (p = 0.001) in treated MS were significant longitudinal decrease; There were no significant longitudinal changes between treated and untreated groups in normalized deep gray matter volume. For QSV, longitudinal increase in the right of PUT (p = 0.022) in the treated MS group and in the left of Hipp (p = 0.045) in the untreated MS group. The QSV and DKI measures were highly correlated with cognitive and disability tests. The treated RRMS patients showed different longitudinal changes of MD value and QSV with untreated in several DGM regions, and these differences were correlated with cognitive and microstructural integrity.

A study of the correlation between gray matter atrophy in multiple sclerosis and impairment of cognitive function domains

Objective: To quantify cerebral cortical and deep gray matter atrophy in patients with multiple sclerosis (MS) and explore its correlation with impairment in domains of cognitive function. Methods: Twenty patients with MS and 16 healthy controls (HC) matched for age, sex, and education level were included. Using FreeSurfer software, based on 3D-MRI technology, the differences in cortical thickness and deep gray matter volume between the two groups were comparatively analyzed. A neuropsychological scale that included six domains of cognitive function was scored on both study groups to analyze the correlation between cortical thickness and volume of deep gray matter in MS patients with impairment in cognitive function domains. Results: Impairment in domains of cognitive function: cognitive impairment was present in 60% MS patients in this study, mainly manifesting as impairment of verbal memory, verbal fluency, visuospatial memory, and information processing speed function (all P<0.05). Of these, the majority had impaired visuospatial memory function (55.0%), and the least number of patients had impaired information processing speed (15.0%). Changes in cortical thickness: compared with the HC group, the MS group showed that cortical atrophy was mainly concentrated in the frontoparietal region, including significant thinning of cortical thickness in the left inferior parietal gyrus, right superior frontal gyrus, and the right superior parietal gyrus (all P<0.05). Among them, atrophy of the left inferior parietal gyrus was significantly positively correlated with the impairment of verbal memory, verbal fluency, and information processing speed (all P<0.05). There was a significant positive correlation between the right superior frontal gyrus atrophy and verbal memory, verbal fluency, and visuospatial memory impairment (all P<0.05). Changes in deep gray matter volume: compared with the HC group, deep gray matter volume in the MS group decreased significantly in the bilateral thalamus, bilateral putamen, bilateral pallidum (all P<0.01), and right nucleus accumbens (P<0.05). Among them, left thalamus atrophy was significantly positively correlated with visuospatial memory impairment (r=0.45, P=0.046), and left putamen atrophy was both significantly positively correlated with visuospatial memory (r=0.45, P=0.047) and information processing speed impairment (r=0.50, P=0.026). Conclusions: Early structural brain changes in MS are dominated by gray matter atrophy. Deep gray matter is more prominent than cortical atrophy.

Grey Matter Atrophy and its Relationship with White Matter Lesions in Patients with Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease, Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder, and Multiple Sclerosis.

To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease. A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported. We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm3); AQP4+NMOSD in the occipital cortex (32.83 cm3); and RRMS diffusely in the GM (260.61 cm3). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm3), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm3). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm3) and AQP4+NMOSD (47.04 cm3). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation. GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288.

Long-term neuroprotective effects of natalizumab and fingolimod in multiple sclerosis: Evidence from real-world clinical data

BackgroundThe long-term effect of high efficacy disease modifying therapy (DMT) on neurodegeneration in people with multiple sclerosis (pwMS) is largely unknown. The aim of this study was to evaluate the long-term effect of natalizumab (NTZ) or fingolimod (FTY) therapy on the evolution of brain atrophy compared to moderate efficacy DMT in a real-world clinical setting. MethodsA total of 438 pwMS with 2,439 MRI exams during treatment were analyzed: 252 pwMS treated with moderate efficacy DMT, 130 with NTZ and 56 with FTY. Evolution of brain atrophy was analyzed over an average follow-up of 6.6 years after treatment initiation. Brain segmentation was performed on clinical 3D-FLAIRs using SynthSeg and regional brain volume changes over time were compared between the treatment groups. ResultsTotal brain, white matter and deep gray matter atrophy rates did not differ between moderate efficacy DMTs, NTZ and FTY. Annualized ventricle growth rates were lower in pwMS treated with NTZ (1.1 %/year) compared with moderate efficacy DMT (2.4 %/year, p < 0.001) and similar to FTY (2.0 %/year, p = 0.051). Cortical atrophy rates were lower in NTZ (-0.08 %/year) compared with moderate efficacy DMT (-0.16 %/year, p = 0.048). ConclusionIn a real-world clinical setting, pwMS treated with NTZ had slower ventricular expansion and cortical atrophy compared to those treated with moderate efficacy DMT.

Enlarged choroid plexus in relapsing-remitting multiple sclerosis may lead to brain structural changes through the glymphatic impairment

ObjectivesTo investigate the potential link among choroid plexus (CP) volume, glymphatic clearance and brain structural change in relapsing-remitting multiple sclerosis (RRMS) patients. Materials and methodsSixty-five RRMS patients and 48 healthy controls (HC) underwent MRI examination. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) was calculated to reflect glymphatic system function. The brain structure volume and DTI-ALPS index were compared between RRMS and HC. The mediating effect of the DTI-ALPS index between CP volume and brain structural changes was further investigated. The longitudinal changes of brain structure and DTI-ALPS index were compared in 20 RRMS patients. ResultsCompared to HC, CP volume in RRMS was significantly increased (P < 0.001), and DTI-ALPS index was significantly decreased (P = 0.001). The volumes of white matter, thalamus, putamen and pallidum were significantly decreased in RRMS, and the volumes of lateral ventricle and third ventricle were increased. Mediation analysis showed DTI-ALPS index partially mediated the association between CP enlargement and deep gray matter (DGM) atrophy in RRMS, and between CP enlargement and ventricle enlargement. CP volume and DTI-ALPS index were also significantly correlated with Expanded Disability Status Scale (EDSS) (P = 0.006, P = 0.043). Notably, the variation of DTI_ALPS index during the follow-up period were significantly and negatively correlated with the variation of EDSS (P = 0.045). ConclusionEnlarged CP volume and decreased DTI_ALPS index may be closely related to DGM atrophy and ventricular enlargement in RRMS, and may be potential imaging markers of clinical disability.

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients

Background and Objective: We explored dynamic changes in the choroid plexus (CP) in patients with relapsing-remitting multiple sclerosis (RRMS) and assessed its relationship with chronic lesion expansion and atrophy in various brain compartments. Methods: Fifty-seven RRMS patients were annually assessed for a minimum of 48 months with 3D FLAIR, pre- and post-contrast 3D T1 and diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline and last follow-up. Results: The volume of CP significantly increased by 1.4% annually. However, the extent of CP enlargement varied considerably among individuals (ranging from −3.6 to 150.8 mm3 or −0.2% to 6.3%). The magnitude of CP enlargement significantly correlated with central (r = 0.70, p < 0.001) and total brain atrophy (r = −0.57, p < 0.001), white (r = −0.61, p < 0.001) and deep grey matter atrophy (r = −0.60, p < 0.001). Progressive CP enlargement was significantly associated with the volume and extent of chronic lesion expansion (r = 0.60, p < 0.001), but not with the number or volume of new lesions. Conclusion: This study provides evidence of progressive CP enlargement in patients with RRMS. Our findings also demonstrate that enlargement of the CP volume is linked to the expansion of chronic lesions and neurodegeneration of periventricular white and grey matter in RRMS patients.

Isolated cognitive impairment in people with multiple sclerosis: frequency, MRI patterns and its development over time

ObjectivesTo study the frequency of isolated (i.e., single-domain) cognitive impairments, domain specific MRI correlates, and its longitudinal development in people with multiple sclerosis (PwMS).Methods348 PwMS (mean age 48 ± 11 years, 67% female, 244RR/52SP/38PP) underwent neuropsychological testing (extended BRB-N) at baseline and at five-year follow-up. At baseline, structural MRI was acquired. Isolated cognitive impairment was defined as a Z-score of at least 1.5 SD below normative data in one domain only (processing speed, memory, executive functioning/working memory, and attention). Multi-domain cognitive impairment was defined as being affected in ≥ 2 domains, and cognitively preserved otherwise. For PwMS with isolated cognitive impairment, MRI correlates were explored using linear regression. Development of isolated cognitive impairment over time was evaluated based on reliable change index.ResultsAt baseline, 108 (31%) PwMS displayed isolated cognitive impairment, 148 (43%) PwMS displayed multi-domain cognitive impairment. Most PwMS with isolated cognitive impairment were impaired on executive functioning/working memory (EF/WM; N = 37), followed by processing speed (IPS; N = 25), memory (N = 23), and attention (N = 23). Isolated IPS impairment was explained by a model of cortical volume and fractional anisotropy (adj. R2 = 0.539, p < 0.001); memory by a model with cortical volume and hippocampal volume (adj. R2 = 0.493, p = 0.002); EF/WM and attention were not associated with any MRI measure. At follow-up, cognitive decline was present in 11/16 (69%) of PwMS with isolated IPS impairment at baseline. This percentage varied between 18 and 31% of PwMS with isolated cognitive impairment in domains other than IPS at baseline.ConclusionIsolated cognitive impairment is frequently present in PwMS and can serve as a proxy for further decline, particularly when it concerns processing speed. Cortical and deep grey matter atrophy seem to play a pivotal role in isolated cognitive impairment. Timely detection and patient-tailored intervention, predominantly for IPS, may help to postpone further cognitive decline.

Enlarged choroid plexus related to iron rim lesions and deep gray matter atrophy in relapsing-remitting multiple sclerosis.

Choroid plexus (CP) is considered to be linked to inflammation of multiple sclerosis (MS), but its connection with markers of inflammation in vivo in MS is unclear, the markers such as lesions load and brain atrophy, particularly the white matter lesions (WMLs) edge surrounded by an iron rim, termed as iron rim lesions (IRLs). To investigate the association between CP volume and brain lesions load, especially IRLs load and atrophy in MS, and its relationship with clinical characteristics. 3.0 T brain MRI images were acquired from 99 relapsing-remitting MS (RRMS) and 60 healthy controls (HCs) to obtain the volumes of CP, whole brain and lesions. Volumes were expressed as a ratio of intracranial volume. Expanded Disability Status Scale (EDSS), Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT) were used to assess the severity of disability and cognitive function. Student's t-test and Multivariable regression analyses were performed to evaluate the difference of CP volumes between RRMS and HC and the association between CP volume and lesions load, brain volumes and clinical scale scores in RRMS. CP volume was 30% larger in patients with RRMS than HCs (p < 0.001) and was 20% larger in patients with IRLs than those without IRLs (p=0.007). Moreover, the larger CP volume was related to greater WMLs volume in the whole RRMS (r=0.46, p < 0.001). Further analysis in patients with IRLs showed a positive correlation between CP volume and WMLs volume (r=0.45, p=0.003), and IRLs volume (r=0.51, p < 0.001). Meanwhile, enlarged CP was related to lower volumes in the whole brain (r=-0.30, p=0.006), deep gray matter (r=-0.51, p < 0.001) and most regional deep gray matter nuclei (except amygdala), but no correlation with cortical lesions or cortex volume (both p > 0.05). In addition, CP volume was significantly higher in patients with cognitive impairment than those with cognitive preservation by MoCA scores (p=0.011); the larger CP volume was associated with higher EDSS scores (r=0.25, p=0.014) and lower SDMT Z scores in RRMS (r=-0.26, p=0.014). The enlargement of CP in RRMS had close correlations with inflammatory lesions, especially IRLs and deep gray matter atrophy, but not the cortex. Meanwhile, the larger CP volume was associated with higher disability and lower cognitive scores. CP volume may be a surrogate imaging marker for MS disease activity.

The association between white matter tract structural connectivity and information processing speed in relapsing-remitting multiple sclerosis

BackgroundInformation processing speed (IPS) deterioration is common in relapsing-remitting multiple sclerosis (RRMS) patients [1] and might severely affect quality of life and occupational activity. However, understanding of its neural substrate is not fully elucidated. We aimed to investigate the associations between MRI-derived metrics of neuroanatomical structures, including the tracts, and IPS.MethodsSymbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Color Trails Test (CTT) were used to evaluate IPS in 73 RRMS consecutive patients, all undergoing only interferon beta (IFN-β) therapy during the study. At the same time, 1.5T MRI including diffusion tensor imaging (DTI) data was acquired for each recruited subject. We analyzed volumetric and diffusion MRI measures (FreeSurfer 6.0) including normalized brain volume (NBV), cortical thickness (thk), white matter hypointensities (WMH), volume (vol), diffusion parameters: mean (MD), radial (RD), axial (AD) diffusivities, and fractional anisotropy (FA) of 18 major white-matter (WM) tracts. Multiple linear regression model with interaction resulted in distinguishing the neural substrate of IPS deficit in the IPS impaired subgroup of patients.ResultsThe most significant tract abnormalities contributing to IPS deficit were right inferior longitudinal fasciculus (R ILF) FA, forceps major (FMAJ) FA, forceps minor (FMIN) FA, R uncinate fasciculus (UNC) AD, R corticospinal tract (CST) FA, and left superior longitudinal fasciculus FA (L SLFT). Among volumetric MRI metrics, IPS deficit was associated with L and R thalamic vol. and cortical thickness of insular regions.ConclusionIn this study, we showed that disconnection of the selected WM tracts, in addition to cortical and deep gray matter (GM) atrophy, might underlie IPS deficit in RRMS patients but more extensive studies are needed for precise associations.

Cognitive impairment in MOGAD is associated with ADEM-like episodes and deep grey matter atrophy (S40.006)

Cognitive impairment in MOGAD is associated with ADEM-like episodes and deep grey matter atrophy (S40.006)

Additional Value of 3-Month Cranial Magnetic Resonance Imaging in Infants with Neonatal Encephalopathy following Perinatal Asphyxia

To assess the evolution of neonatal brain injury noted on magnetic resonance imaging (MRI), develop a score to assess brain injury on 3-month MRI, and determine the association of 3-month MRI with neurodevelopmental outcome in neonatal encephalopathy (NE) following perinatal asphyxia. Retrospective single-center study including 63 infants with perinatal asphyxia and NE (n=28 cooled) with cranial MRI <2 weeks and 2-4 months after birth. Both scans were assessed using biometrics, a validated injury score for neonatal MRI, and a new score for 3-month MRI, with a white matter (WM), deep gray matter (DGM), and cerebellum sub-score. The evolution of brain lesions was assessed, and both scans were related to 18-24 month composite outcome. Adverse outcomes included cerebral palsy, neurodevelopmental delay, hearing/visual impairment, and epilepsy. Neonatal DGM injury generally evolved into DGM atrophy and focal signal abnormalities, and WM/watershed injury evolved into WM and/or cortical atrophy. While the neonatal total and DGM scores were associated with composite adverse outcomes, the 3-month DGM score (OR 1.5, 95% CI 1.2 - 2.0) and WM score (OR 1.1, 95% CI 1.0 - 1.3) were also associated with composite adverse outcomes (occurring in n=23). The 3-month multivariable model (including the DGM and WM sub-scores) had higher positive (0.88 versus 0.83) but lower negative predictive value (0.83 versus 0.84) than neonatal MRI. Inter-rater agreement for the total, WM, and DGM 3-month score was 0.93, 0.86, and 0.59. Especially DGM abnormalities on 3-month MRI, preceded by DGM abnormalities on the neonatal MRI, were associated with 18-24 month outcome, indicating utility of 3-month MRI for treatment evaluation in neuroprotective trials. However, the clinical usefulness of 3-month MRI seems limited compared with neonatal MRI.

Effect of deep gray matter atrophy on information processing speed in early relapsing-remitting multiple sclerosis.

Cognitive dysfunction, including reduced Information processing speed (IPS), is relatively common in multiple sclerosis(MS). IPS deficits have profound effects on several aspects of patients' life. Previous studies showed that deep gray matter atrophy is highly correlated with overall cognitive impairment in MS. However, the effect of deep gray matter atrophy on IPS deficits is not well understood. In this study, we evaluated the effects of deep gray matter volume changes on IPS in people with early relapse-remitting MS (RRMS) compared to healthy control. In this case-control study, we enrolled 63 case with RRMS and 36 healthy controls. All patients were diagnosed within 6 years. IPS was evaluated using the Integrated Cognitive Assessment (ICA) test. We also performed a 1.5T MRI to evaluate deep gray matter structures. People with RRMS had lower accuracy in the ICA test (p=.01). However, the reaction time did not significantly differ between RRMS and control groups (p=.6). Thalamus volume was significantly lower in the RRMS group with impaired IPS compared to the RRMS with normal IPS and control groups (p<10-4). Other deep gray matter structures were not significantly different between the RRMS with impaired IPS group and the RRMS with normal IPS group. Some people with MS are impaired in IPS even in the early stages of the disease. Thalamic atrophy affected IPS in these patients, however atrophy in other deep gray matter structures, including caudate, putamen, globus pallidus, hippocampus, amygdala, accumbens, and cerebellum, were not significantly correlated with IPS impairment in early RRMS.

Regional white matter and gray matter damage and cognitive performances in multiple sclerosis according to sex.

In this study, we investigated whether regional distribution of white matter (WM) lesions, normal-appearing [NA] WM microstructural abnormalities and gray matter (GM) atrophy may differently contribute to cognitive performance in multiple sclerosis (MS) patients according to sex. Using the same scanner, brain 3.0T MRI was acquired for 287 MS patients (females = 173; mean age = 42.1 [standard deviation, SD = 12.7] years; relapsing-remitting = 196, progressive = 91; median Expanded Disability Status Scale = 2.5 [interquartile range, IQR = 1.5-5.0]; median disease duration = 12.1 [IQR = 6.3-19.0] years; treatment: none = 70, first-line = 130, second-line = 87) and 172 healthy controls (HC) (females = 92; mean age = 39.3 [SD = 14.8] years). MS patients underwent also Rao's neuropsychological battery. Using voxel-wise analyses, we investigated in patients sex-related differences in the association of cognitive performances with WM lesions, NAWM fractional anisotropy (FA) and GM volumes (p < 0.01, family-wise error [FWE]). Sixty-six female (38%) and 48 male (42%) MS patients were cognitively impaired, with no significant between-group difference (p = 0.704). However, verbal memory performance was worse in males (p = 0.001), whereas verbal fluency performance was worse in females (p = 0.004). In both sexes, a higher T2-hyperintense lesion prevalence in cognitively-relevant WM tracts was significantly associated with worse cognitive performance (p ≤ 0.006), with stronger associations in females than males in global cognition (p ≤ 0.004). Compared to sex-matched HC, male and female MS patients had widespread lower NAWM FA and GM volume (p < 0.01). In both sexes, worse cognitive performance was associated with widespread reduced NAWM FA (p < 0.01), with stronger associations in females than males in global cognition and verbal memory (p ≤ 0.009). Worse cognitive performance was significantly associated with clusters of cortical GM atrophy in males (p ≤ 0.007) and mainly with deep GM atrophy in females (p ≤ 0.006). In this study, only limited differences in cognitive performances were found between male and female MS patients. A disconnection syndrome due to focal WM lesions and diffuse NAWM microstructural abnormalities seems to be more relevant in female MS patients to explain cognitive impairment.

Importance of Identifying Cognitive Impairment in Multiple Sclerosis.

This article aims to highlight the impact of cognitive impairment on outcomes and quality of life for people with multiple sclerosis (MS) and to review current evidence for the efficacy of disease-modifying therapies (DMTs) and other interventions. In addition, we provide clinical practice insights regarding screening and management of cognitive impairment in people with MS. Evidence suggests that cognitive deterioration often accompanies magnetic resonance imaging changes. Neocortical volume and deep grey matter atrophy correlate with cognitive impairment. Similarly, cognitive decline is predictive of a higher lesion burden. Cognitive impairment is an important clinical measure of disability and negatively impacts quality of life. Phase 3 studies suggest that DMTs such as natalizumab, ozanimod and fingolimod may provide long-lasting, clinically meaningful effects on cognition in people with MS. Further data are needed to support the use of adjunct cognitive behavioural and exercise interventions for people with MS who have cognitive impairment. More data are needed to define appropriate management strategies for cognitive impairment in people with MS. Baseline and periodic screening for cognitive impairment and inclusion of cognitive impairment as a clinical trial endpoint will help to inform efforts to manage this important aspect of MS.

Magnetic Resonance Imaging Evaluation of Perivascular Space Abnormalities in Neuromyelitis Optica

ObjectiveAstrocytes outline the perivascular space (PVS) and regulate fluid exchange through the aquaporin‐4 water channel. As neuromyelitis optica is an autoimmune astrocytopathy targeting aquaporin‐4, we hypothesized that it could be associatied with PVS abnormalities.MethodsA total of 34 patients, and 46 age‐ and sex‐matched healthy controls from two independent cohorts (exploratory and validation dataset) underwent a standardized 3.0‐T magnetic resonance imaging protocol including conventional and diffusion tensor imaging. Susceptibility‐weighted imaging was also acquired in the exploratory dataset. We evaluated macroscopic and microstructural abnormalities of PVS in terms of enlargement and water diffusivity (DTI‐ALPS index). In the exploration dataset, a susceptibility‐weighted sequence was used to draw the regions of interest for the DTI‐ALPS index calculation in areas having veins perpendicular to lateral ventricles. Between‐group comparisons, correlations, and regression models were run to assess associations between PVS abnormalities, and clinical and magnetic resonance imaging variables.ResultsPatients had a higher frequency of severe PVS enlargement in the centrum semiovale (29.4% vs 8.7%), which correlated with brain atrophy, deep grey matter atrophy, and poorer cognitive performance (r‐values range: −0.44, −0.36; p values: 0.01–0.046).In both datasets, patients had reduced DTI‐ALPS index compared with controls (p values 0.004–0.038). Lower DTI‐ALPS index, deep gray matter volume, and cortical volume could discriminate between patients and controls (R 2 = 0.62), whereas lower DTI‐ALPS index, higher number of myelitis, and higher T2‐lesion volume were associated with worse disability (R 2 = 0.55).InterpretationPatients with neuromyelitis optica spectrum disorder are characterized by abnormal enlargement and impaired water diffusion along the PVS, whose clinical implications suggest a direct correlation with disease pathogenesis and severity. ANN NEUROL 2022;92:173–183

Time course of lesion-induced atrophy in multiple sclerosis.

White matter (WM) tract disruption impacts volume loss in connected deep gray matter (DGM) over 5years in people with multiple sclerosis (PwMS). However, the timeline of this phenomenon remains poorly characterized. Annual serial MRI for 181 PwMS was retrospectively analyzed from a 10-year clinical trial database. Annualized thalamic atrophy, DGM atrophy, and disruption of connected WM tracts were measured. For time series analysis, ~700 epochs were collated using a sliding 5-year window, and regression models predicting 1-year atrophy were applied to characterize the influence of new tract disruption from preceding years, while controlling for whole brain atrophy and other relevant factors. Disruptions of WM tracts connected to the thalamus were significantly associated with thalamic atrophy 1year later (β: 0.048-0.103). This effect was not observed for thalamic tract disruption concurrent with the time of atrophy nor for thalamic tract disruption preceding the atrophy by 2-4years. Similarly, disruptions of white matter tracts connected to the DGM were significantly associated with DGM atrophy 1year later (β: 0.078-0.111), but not for tract disruption concurrent with, nor preceding the atrophy by 2-4years. Increased rates of thalamic and DGM atrophy were restricted to 1year following newly developed disruption in connected WM tracts. In research and clinical settings, additional gray matter atrophy may be expected 1year following new lesion growth in connected white matter.

Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability.

Recent evidence has shown the existence of a CNS 'waste clearance' system, defined as the glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inflammatory processes. We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex-matched healthy control subjects. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep grey matter volume, white and cortical grey matter lesion volume and normal-appearing white matter microstructural damage. Multiple sclerosis patients showed an overall lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.06, P = 0.04 for relapsing-remitting and -0.19, P = 0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index versus relapsing-remitting multiple sclerosis patients (estimated mean difference: -0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = -0.45, P = 0.001) and longer disease duration (r = -0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the first 4.13 years of the disease course (r = -0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = -0.36, P = 0.003) and cortical (r = -0.41, P = 0.001) lesion volume, more severe cortical (r = 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) grey matter atrophy, reduced fractional anisotropy (r = 0.42, P = 0.001) and increased mean diffusivity (r = -0.45, P = 0.001) in the normal-appearing white matter. Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reflects a more severe clinical disability. These findings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation.

Odor Identification and Regional Gray Matter Atrophy in Patients with Alzheimer's Disease, Parkinson's Disease, and the Healthy Elderly: A Cross-Sectional Structural MRI Study.

Multiple associations between impaired olfactory performance and regional cortical and deep gray matter atrophy have been reported in separate studies of patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), and of the healthy elderly. We aimed to evaluate such possible associations among these populations in a unified manner. Twenty AD, twenty PD patients’ and twenty healthy age- and sex-matched controls’ odor identification performance was assessed with the Lithuanian adaptation of the Sniffin’ Sticks 12 odor identification test, followed by morphometric gray matter analysis by MRI using FreeSurfer. AD patients had significantly lower cognitive performance than both PD patients and the healthy elderly, as evaluated with the Mini-Mental State Examination (MMSE). Odor identification performance was significantly worse in AD and PD patients compared with the healthy elderly; AD patients performed slightly worse than PD patients, but the difference was not statistically significant. Among patients with AD, worse odor identification performance was initially correlated with atrophy of multiple cortical and deep gray matter regions known to be involved in olfactory processing, however, only two measures—decreased thicknesses of the right medial and left lateral orbitofrontal cortices—remained significant after adjustment for possible confounders (age, MMSE score, and global cortical thickness). Among patients with PD and the healthy elderly we found no similar statistically significant correlations. Our findings support the key role of the orbitofrontal cortex in odor identification among patients with AD, and suggest that correlations between impaired odor identification performance and regional gray matter atrophy may be relatively more pronounced in AD rather than in PD.

Unraveling Deep Gray Matter Atrophy and Iron and Myelin Changes in Multiple Sclerosis.

Modifications of magnetic susceptibility have been consistently demonstrated in the subcortical gray matter of MS patients, but some uncertainties remain concerning the underlying neurobiological processes and their clinical relevance. We applied quantitative susceptibility mapping and longitudinal relaxation rate relaxometry to clarify the relative contribution of atrophy and iron and myelin changes to deep gray matter damage and disability in MS. Quantitative susceptibility mapping and longitudinal relaxation rate maps were computed for 91 patients and 55 healthy controls from MR images acquired at 3T. Applying an external model, we estimated iron and myelin concentration maps for all subjects. Subsequently, changes of deep gray matter iron and myelin concentration (atrophy-dependent) and content (atrophy-independent) were investigated globally (bulk analysis) and regionally (voxel-based and atlas-based thalamic subnuclei analyses). The clinical impact of the observed MRI modifications was evaluated via regression models. We identified reduced thalamic (P < .001) and increased pallidal (P < .001) mean iron concentrations in patients with MS versus controls. Global myelin and iron content in the basal ganglia did not differ between the two groups, while actual iron depletion was present in the thalamus (P < .001). Regionally, patients showed increased iron concentration in the basal ganglia (P ≤ .001) and reduced iron and myelin content in thalamic posterior-medial regions (P ≤ .004), particularly in the pulvinar (P ≤ .001). Disability was predicted by thalamic volume (B = -0.341, P = .02), iron concentration (B = -0.379, P = .005) and content (B = -0.406, P = .009), as well as pulvinar iron (B = -0.415, P = .003) and myelin (B = -0.415, P = .02) content, independent of atrophy. Quantitative MRI suggests an atrophy-related iron increase within the basal ganglia of patients with MS, along with an atrophy-independent reduction of thalamic iron and myelin correlating with disability. Absolute depletions of thalamic iron and myelin may represent sensitive markers of subcortical GM damage, which add to the clinical impact of thalamic atrophy in MS.