Local brain atrophy accounts for functional activity differences in normal aging

Neurodegenerative changes are key manifestations of Wilson disease (WD), causing neurological symptoms including parkinsonism, tremors, and dystonia. However, the neuroimaging correlates of specific neurological manifestations (especially dystonia) in WD remain poorly characterized. 37 WD patients and 37 healthy controls (HC) were recruited. All subjects underwent structural magnetic resonance scanning, muscle biomechanical measurements, and the Unified Wilson Disease Rating Scale for Neurology (UWDRS-N) assessment. Neurodegenerative changes, identified as gray matter volume (GV) changes, were analyzed via voxel-based morphometry (VBM) in WD compared to HC. Clinical symptoms were linked to GV changes in WD patients' brains. Compared with HC, WD patients had GV loss in the bilateral caudate nucleus, putamen, cerebellum (Crus1), left amygdala, right posterior insular lobe, and right parahippocampal gyrus and increased GV in the bilateral anterior insular lobes. In cortical areas, UWDRS-N significantly negatively correlated with GV in the bilateral posterior insula lobes, part of temporal lobe, optic cortex, frontal lobe, and cingulate cortex, while positively correlated with that in bilateral anterior insular lobes and putamen. Moreover, the GV from the left parahippocampal gyrus, bilateral hippocampus, and bilateral caudate nucleus showed a strong positive correlation with the F value of the right gastrocnemius medial head. In WD patients with neurological symptoms, obvious abnormal GV values in the cortico-striatal-thalamo-cortical (CSTC) circuit were noted. These GV changes were linked to UWDRS-N and correlated with muscle tension. The study mapped UWDRS-N and muscle biomechanics in GV-impaired areas, suggesting altered GV (especially in basal ganglia) as a key imaging sign of WD severity. This indicates that the CSTC circuit could act as a biomarker for WD neurological symptoms and affect WD dystonia mechanisms. Additionally, it shows that muscle-related biological parameters can assess WD dystonia severity and neurological damage. clinicaltrials.gov, identifier NCT05305872.

Reductions in body weight and insulin resistance are not associated with changes in grey matter volume or cortical thickness during the PREVIEW study

Age-dependent cut-offs for pathological deep gray matter and thalamic volume loss using Jacobian integration

Association between change in brain gray matter volume, cognition, and depression severity: Pre- and post- antidepressant pharmacotherapy for late-life depression

Background and purposeMeasures of atrophy in the whole brain can be used to reliably assess treatment effect in clinical trials of patients with multiple sclerosis (MS). Trials assessing the effect of treatment on grey matter (GM) and white matter (WM) atrophy are very informative, but hindered by technical limitations. This study aimed to measure GM and WM volume changes, using a robust longitudinal method, in patients with relapsing MS randomized to cladribine tablets 3.5 mg/kg or placebo in the CLARITY study.MethodsWe analysed T1‐weighted magnetic resonance sequences using SIENA‐XL, from 0 to 6 months (cladribine, n = 267; placebo, n = 265) and 6 to 24 months (cladribine, n = 184; placebo, n = 186). Mean percentage GM and WM volume changes (PGMVC and PWMVC) were compared using a mixed‐effect model.ResultsMore GM and WM volume loss was found in patients taking cladribine versus those taking placebo in the first 6 months of treatment (PGMVC: cladribine: −0.53 vs. placebo: −0.25 [p = 0.045]; PWMVC: cladribine: −0.49 vs. placebo: −0.34 [p = 0.137]), probably due to pseudoatrophy. However, over the period 6 to 24 months, GM volume loss was significantly lower in patients on cladribine than in those on placebo (PGMVC: cladribine: −0.90 vs. placebo: −1.27 [p = 0.026]). In this period, volume changes in WM were similar in the two treatment arms (p = 0.52).ConclusionsAfter a short period of pseudoatrophy, treatment with cladribine 3.5 mg/kg significantly reduced GM atrophy in comparison with placebo. This supports the relevance of GM damage in MS and may have important implications for physical and cognitive disability progression.

This study aimed to explore gray matter volume (GMV) changes in patients undergoing hemodialysis and assess the clinical risk factors associated with GMV changes and the relationship between GMV changes and neuropsychologic test results. Eighty-eight hemodialysis patients and 76 healthy controls (HCs) were recruited in this study. Fifty patients underwent follow-up examinations (follow-up duration: 1.75 ± 0.55 years), including magnetic resonance imaging, blood biochemical, and neuropsychologic testing. Changes in GMV between the patients and HCs were assessed. Longitudinal GMV changes were also explored in the patients. The clinical risk factors associated with longitudinal GMV changes and the correlations between longitudinal GMV changes and neuropsychologic test results were analyzed in the patients. Patients undergoing hemodialysis had diffusely decreased GMV compared with HCs (with age, sex, and total intracranial volume [TIV] as covariates, P<0.001, voxel-wise threshold false discovery rate [FDR] corrected). Compared with patients at baseline, regional decreased GMV were found in patients at follow-up (with age and TIV as covariates, P<0.05, voxel-wise threshold FDR corrected). Increased serum urea concentrations, parathyroid hormone levels, and hemodialysis duration were independent risk factors for decreased GMV in patients undergoing hemodialysis (all P<0.05, FDR corrected). Patients undergoing hemodialysis had lower mini-mental state examination (MMSE) (27[26, 29]) and Montreal cognitive assessment (MoCA) (22[19.5, 24.0]) scores than those of the HCs (30[29, 30] and 28[26.9, 29]) (all P<0.05). The MMSE scores of the patients at follow-up (26[25, 28.5]) were lower than those of patients at baseline (28[25, 29.5]) (P=0.02). The decreased left caudate volumes were positively correlated with reduced MMSE scores in hemodialysis patients (rs=0.437, P=0.033). Patients undergoing hemodialysis had noticeable GM atrophy over time, related to cognitive impairments.

Sex differences in functional brain activation during noxious visceral stimulation in rats

To explore cross-sectional and longitudinal gray matter (GM) volume changes in patients with migraine and their association with patients' clinical characteristics and disease activity. Brain T2-weighted and 3-dimensional T1-weighted scans were acquired from 73 episodic migraineurs and 46 age- and sex-matched nonmigraine controls at baseline. Twenty-four migraineurs and 25 controls agreed to be reexamined after a mean follow-up of 4 years. Using a general linear model and SPM12, a whole-brain analysis was performed to assess GM volume modifications. At baseline, compared to controls, patients with migraine showed lower cerebellar GM volume and higher volume of regions of the frontotemporal lobes. At follow-up, migraineurs were significantly older than controls. Over the follow-up, migraineurs developed an increased volume of frontotemporoparietal regions, which was more prominent in patients with a higher baseline disease activity: long disease duration and high attack frequency. Migraineurs also developed decreased GM volume of visual areas, which was related to higher pain severity. Patients with an increased attack frequency at follow-up experienced both increased and decreased volume of nociceptive regions. In migraineurs, reduced GM volume of extrastriate visual areas during the follow-up was significantly correlated to baseline disease activity: shorter disease duration and lower attack frequency. In this cohort, the migraine brain changes dynamically over time, and different pathophysiologic mechanisms can occur in response to patients' disease severity. The interaction between predisposing brain traits and experience-dependent responses might vary across different nociceptive and visual areas, thus leading to distinct patterns of longitudinal GM volume changes.

Affective facial processing is an important component of interpersonal relationships, which is altered in patients with major depression. The study was designed to examine differences in functional brain activity between patients with major depression and healthy controls using functional magnetic resonance imaging (fMRI). Twelve patients with major depression and 12 age-, gender- and handedness-matched healthy controls were studied using fMRI. Subjects had to match facial emotional expressions in explicit trials, and gender of the presented faces in implicit trials. Patients showed higher blood oxygen level-dependent (BOLD) responses to implicit emotional stimuli than healthy controls in the left dorsolateral prefrontal cortex and the left precentral gyrus. Patients show a failure of deactivation in ACC, right dorsolateral prefrontal cortex (DLPFC) and right superior frontal cortex. Moreover, they exhibited smaller differences in BOLD responses in the left superior temporal lobe for the implicit contrasted to the explicit task, and in the cerebellum for the explicit contrasted to the implicit task compared to those of controls. Altered activation of the prefrontal cortex and anterior cingulum during emotion processing is a key feature of major depression.

Objective:Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and memory dysfunction. This study aims to explore changes of gray matter volume and their relationship with cognitive and memory function in AD patients using magnetic resonance imaging-based analysis.Methods:This retrospective study analyzed the clinical data from 80 AD patients (AD group) and 45 patients with mild cognitive impairment (MCI group) treated in the hospital between January 2021 and December 2022. Furthermore, 43 healthy adults (control group) were also included for comparison. All the participants underwent a brain magnetic resonance imaging (MRI) examination. These three groups were comparatively analyzed for brain MRI imaging characteristics, changes of gray matter volume, as well as their cognitive and memory functions. Based on gray matter volume, AD patients were divided into the low-volume (37 cases) and high-volume (43 cases) groups using the K-mean clustering method. Furthermore, changes of cognitive and memory function across these two subgroups were compared. The correlation among gray matter volume, cognitive, and memory function across AD patients was assessed using Pearson correlation analysis. Additionally, predictive abilities of gray matter volume in severe cognitive impairment were determined employing receiver operating characteristic (ROC) curve analysis.Results:The gray matter volume, percentage of gray matter volume, scores of mini-mental state examination (MMSE), and California verbal learning test (CVLT-II) were significantly decreased across the control, MCI, and AD groups (p < 0.05). Compared to the control group, gray matter volume was reduced in the AD and MCI groups. Compared to the high-volume group, gray matter volume, percentage of gray matter volume, scores of MMSE and CVLT-II were decreased in the low-volume group (p < 0.05). Gray matter volume and gray matter volume percentage were positively correlated with scores of MMSE, immediate memory, delayed recall, cue recall, and long-delayed recognition (gray matter volume r = 0.384/0.334/0.308/0.251/0.333; percentage of gray matter volume r = 0.584/0.319/0.299/0.257/0.298; p < 0.001). The area under curve (AUC) for gray matter volume and gray matter volume percentage in predicting severe cognitive impairment were 0.833 (95% CI: 0.747–0.919) and 0.810 (95% CI: 0.715–0.904), respectively (p < 0.001), with sensitivity of 95.24% and 90.48%, and specificity of 66.10% and 67.80%, respectively.Conclusion:MRI is a useful tool for evaluating changes of gray matter volume in AD patients. The changes in gray matter volume are strongly correlated with cognitive and memory functions, which serve as a reliable predictor of severe cognitive impairment in AD patients. Furthermore, MRI provides robust imaging evidence for identifying AD patients at risk of severe cognitive impairment.

Gray Matter Volume Changes over the Whole Brain in the Bulbar- and Spinal-onset Amyotrophic Lateral Sclerosis: a Voxel-based Morphometry Study.

Association between a longer duration of illness, age and lower frontal lobe grey matter volume in schizophrenia

BackgroundThe driving mechanisms of structural brain alterations in the earliest stages of Alzheimer's disease (AD) are not well understood. Previous heterogeneous findings in preclinical AD, including subtle atrophy and also increased grey matter (GM) volume, underscore the need for further exploration. This study uses an extensive fluid biomarkers panel to identify pathological drivers behind longitudinal GM changes in cognitively unimpaired (CU) adults.MethodWe investigated 632 CU individuals (age 61.8±6.3, mean±SD) from the ALFA+, Wisconsin ADRC, and WRAP cohorts (Table 1), with available longitudinal MRI and cerebrospinal fluid biomarkers of Aß42/40, p‐tau181, neurogranin, NfL, total‐tau, a‐synuclein, GFAP, YKL‐40, sTREM2, s100B, and IL‐6 measured using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd). We used non‐negative matrix factorization to decompose biomarkers into latent components. The per‐subject component weights were associated with voxel‐wise GM volume changes (years 3.5±0.9, mean±SD) and longitudinal performance on the preclinical Alzheimer's cognitive composite (PACC) using mixed model analysis.ResultSix biomarker components (C1‐C6) were identified (Figure 1). High expression of astrocyte biomarkers (C1) was related to GM volume increases in frontotemporal and subcortical regions, and faster cognitive decline in A+ individuals, while axonal damage with glial reactivity (C2) was associated with temporal atrophy. Microglial reactivity (C3) showed subtle associations with both increases and decreases in GM volume in different regions. A component primarily based on Aß pathology (C4) was strongly associated with widespread GM volume loss and faster cognitive decline. IL‐6 (C5) reflected non‐AD related inflammation. Finally, the co‐expression of tau pathology, neuronal injury, and synaptic damage (C6) showed robust associations with frontotemporal atrophy and cognitive decline in A+ individuals.ConclusionIn a large longitudinal sample, we provide in vivo evidence that in the earliest stages of AD, Aß pathology is also a strong contributor to future neuronal loss and cognitive decline besides neurofibrillary tangles and neuroaxonal damage. Astroglial reactivity (i.e. GFAP, s100B) in preclinical AD was associated with an increase in GM volume, which may suggest a neuroinflammatory response, and was associated with worse cognitive performance. These findings underscore the dynamic nature of structural brain changes within preclinical AD, shaped by the contributions from diverse pathophysiological processes.

In animal models of Parkinson's disease (PD), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most widely used agents that damages the nigrostriatal dopaminergic pathway. However, brain structural changes in response to MPTP remain unclear. This study aimed to investigate in vivo longitudinal changes in gray matter (GM) volume and white matter (WM) microstructure in primate models administered with MPTP. In six cynomolgus monkeys, high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) scans were acquired 7 times over 32 weeks, and assessments of motor symptoms were conducted over 15 months, before and after the MPTP injection. Changes in GM volume and WM microstructure were estimated on a voxel-by-voxel basis. Mixed-effects regression models were used to examine the trajectories of these structural changes. GM volume initially increased after the MPTP injection and gradually decreased in the striatum, midbrain, and other dopaminergic areas. The cerebellar volume temporarily decreased and returned to its baseline level. The rate of midbrain volume increase was positively correlated with the increase rate of motor symptom severity (Spearman rho = 0.93, p = 0.008). Mean, axial, and radial diffusivity in the striatum and frontal areas demonstrated initial increases and subsequent decreases. The current multi-modal imaging study of MPTP-administered monkeys revealed widespread and dynamic structural changes not only in the nigrostriatal pathway but also in other cortical, subcortical, and cerebellar areas. Our findings may suggest the need to further investigate the roles of inflammatory reactions and glial activation as potential underlying mechanisms of these structural changes.

The donepezil treatment is associated with improved cognitive performance in patients with mild cognitive impairment (MCI), and its clinical effectiveness is well-known. However, the impact of the donepezil treatment on the enhanced white matter connectivity in MCI is still unclear. The purpose of this study was to evaluate the thalamo-cortical white matter (WM) connectivity and cortical thickness and gray matter (GM) volume changes in the cortical regions following donepezil treatment in patients with MCI using probabilistic tractography and voxel-based morphometry. Patients with MCI underwent magnetic resonance examinations before and after 6-month donepezil treatment. Compared with healthy controls, patients with MCI showed decreased WM connectivity of the thalamo-lateral prefrontal cortex, as well as reduced thickness in the medial/lateral orbitofrontal cortices (p < 0.05). The thalamo-lateral temporal cortex connectivity in patients with MCI was negatively correlated with Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) (r = −0.76, p = 0.01). The average score of the Korean version of the mini-mental state examination (K-MMSE) in patients with MCI was improved by 7.9% after 6-months of donepezil treatment. However, the patterns of WM connectivity and brain volume change in untreated and treated patients were not significantly different from each other, resulting from multiple comparison corrections. These findings will be valuable in understanding the neurophysiopathological mechanism on MCI as a prodromal phase of Alzheimer's disease in connection with brain functional connectivity and morphometric change.