Wilson disease (WD) primarily presents with hepatic and neurological symptoms. While hepatic symptoms typically precede the neurological manifestations, copper accumulates in the brain already in this patient group and leads to subclinical brain MRI abnormalities including T2 hyperintensities and atrophy. This study aimed to assess brain morphological changes in mild hepatic WD. WD patients without a history of neurologic symptoms and decompensated cirrhosis and control participants underwent brain MRI at 3T scanner including high-resolution T1-weighted images. A volumetric evaluation was conducted on the following brain regions: nucleus accumbens, caudate, pallidum, putamen, thalamus, amygdala, hippocampus, midbrain, pons, cerebellar gray matter, white matter (WM), and superior peduncle, using Freesurfer v7 software. Whole-brain analyses using voxel- and surface-based morphometry were performed using SPM12. Statistical comparisons utilized a general linear model adjusted for total intracranial volume, age, and sex. Twenty-six WD patients with mild hepatic form (30 ± 9 years [mean age ± SD]); 11 women; mean treatment duration 13 ± 12 (range 0-42) years and 28 healthy controls (33 ± 9 years; 15 women) were evaluated. Volumetric analysis revealed a significantly smaller pons volume and a trend for smaller midbrain and cerebellar WM in WD patients compared to controls. Whole-brain analysis revealed regions of reduced volume in the pons, cerebellar, and lobar WM in the WD group. No significant differences in gray matter density or cortical thickness were found. Myelin or WM in general seems vulnerable to low-level copper toxicity, with WM volume loss showing promise as a marker for assessing brain involvement in early WD stages.
- MeSH
- bílá hmota patologie diagnostické zobrazování MeSH
- dospělí MeSH
- hepatolentikulární degenerace * patologie diagnostické zobrazování MeSH
- játra patologie diagnostické zobrazování MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mladý dospělý MeSH
- mozek * patologie diagnostické zobrazování MeSH
- šedá hmota patologie diagnostické zobrazování MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cerebellar atrophy is a characteristic sign of late-onset Tay-Sachs disease (LOTS). Other structural neuroimaging abnormalities are inconsistently reported. Our study aimed to perform a detailed whole-brain analysis and quantitatively characterize morphometric changes in LOTS patients. Fourteen patients (8 M/6F) with LOTS from three centers were included in this retrospective study. For morphometric brain analyses, we used deformation-based morphometry, voxel-based morphometry, surface-based morphometry, and spatially unbiased cerebellar atlas template. The quantitative whole-brain morphometric analysis confirmed the finding of profound pontocerebellar atrophy with most affected cerebellar lobules V and VI in LOTS patients. Additionally, the atrophy of structures mainly involved in motor control, including bilateral ventral and lateral thalamic nuclei, primary motor and sensory cortex, supplementary motor area, and white matter regions containing corticospinal tract, was present. The atrophy of the right amygdala, hippocampus, and regions of occipital, parietal and temporal white matter was also observed in LOTS patients in contrast with controls (p < 0.05, FWE corrected). Patients with dysarthria and those initially presenting with ataxia had more severe cerebellar atrophy. Our results show predominant impairment of cerebellar regions responsible for speech and hand motor function in LOTS patients. Widespread morphological changes of motor cortical and subcortical regions and tracts in white matter indicate abnormalities in central motor circuits likely coresponsible for impaired speech and motor function.
- MeSH
- centrální nervový systém anatomie a histologie fyziologie MeSH
- disekce MeSH
- elektroencefalografie MeSH
- lidé MeSH
- mozek * anatomie a histologie chirurgie fyziologie patologie MeSH
- neurozobrazování metody MeSH
- poruchy vědomí MeSH
- teoretické modely MeSH
- vědomí fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Few studies on multiple sclerosis (MS) have explored the variability of percentage brain volume change (PBVC) measurements obtained from different clinical MRIs. In a retrospective multicentre cohort study, we quantified the variability of annualised PBVC in clinical MRIs. METHODS: Clinical MRIs of relapse-onset MS patients were assessed by icobrain. Volumetric data were analysed on same-scanner and different-scanner MRI pairs if they passed quality control criteria. Alignment similarity between two images had to be comparable to same-scanner scan-rescan images. RESULTS: Of 6826 MRIs, 85 % had appropriate volumetric sequences and 4446 serial MRI pairs were analysed. 3334 (75 %) MRI pairs from 1207 patients met the inclusions. The PBVC of included MRI pairs showed variance of 0.78 % for same-scanner pairs and 0.80 % for different-scanner pairs. Further selection of included MRI pairs with the best variance resulted in 1885 (42 %) MRI pairs with PBVC variance of 0.34 %. Excluded MRI pairs with poor alignment similarity had variances of 2.97 % for same-scanner pairs and 20.79 % for different-scanner pairs. CONCLUSION: Icobrain should be utilised for PBVC determination only on selected MRIs with the best alignment similarity. Applying strict selection criteria for the included MRI pairs and longitudinal imaging on the same scanner remain mandatory to reduce PBVC variability.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mozek * diagnostické zobrazování patologie MeSH
- relabující-remitující roztroušená skleróza diagnostické zobrazování farmakoterapie patologie MeSH
- retrospektivní studie MeSH
- roztroušená skleróza diagnostické zobrazování patologie MeSH
- velikost orgánu MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
BACKGROUND AND OBJECTIVES: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS. METHODS: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS). RESULTS: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes (B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (ΔR2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change (r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (ΔR2 = 0.064, p < 0.001). DISCUSSION: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.
- MeSH
- deep learning * MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- magnetická rezonanční tomografie * MeSH
- mozek * diagnostické zobrazování patologie MeSH
- neurodegenerativní nemoci diagnostické zobrazování MeSH
- průřezové studie MeSH
- retrospektivní studie MeSH
- roztroušená skleróza * diagnostické zobrazování patologie MeSH
- stárnutí * patologie fyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.
- MeSH
- exekutivní funkce * fyziologie MeSH
- frontotemporální demence * patologie diagnostické zobrazování patofyziologie psychologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mozek diagnostické zobrazování patologie MeSH
- neuropsychologické testy * MeSH
- průřezové studie MeSH
- senioři MeSH
- sociální kognice MeSH
- teorie mysli * fyziologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: This study aimed to investigate relationships between cholesterol profile, brain volumetric MRI, and clinical measures in a large observational cohort of multiple sclerosis (MS) patients. MATERIALS AND METHODS: We included 1.505 patients with 4.966 time points including complete lipid, clinical, and imaging data. The time among lipid, brain MRI and clinical measures was under 90 days. Cross-sectional statistical analysis at baseline was performed using an adjusted linear regression and analysis of longitudinal lipid and MRI measures data was performed using adjusted linear mixed models. RESULTS: We found associations between higher high-density lipoprotein cholesterol (HDL-C) and lower brain parenchymal fraction (BPF) at cross-sectional analysis at baseline (B = -0.43, CI 95%: -0.73, -0.12, p = 0.005), as well as in longitudinal analysis over follow-up (B = -0.32 ± 0.072, χ2 = 36.6; p = < 0.001). Higher HDL-C was also associated with higher T2-lesion volume in longitudinal analysis (B = 0.11 ± 0.023; χ2 = 23.04; p = < 0.001). We observed a weak negative association between low-density lipoprotein cholesterol (LDL-C) levels and BPF at baseline (B = -0.26, CI 95%: -0.4, -0.11, p = < 0.001) as well as in longitudinal analysis (B = -0.06 ± 0.03, χ2 = 4.46; p = 0.03). T2-LV did not show an association with LDL-C. We did not find any association between lipid measures and disability. The effect of lipid levels on MRI measures and disability was minimal (Cohen f2 < 0.02). CONCLUSIONS: Our results contradict the previously described exclusively positive effect of HDL-C on brain atrophy in patients with MS. Higher LDL-C was weakly associated with higher brain atrophy but not with higher lesion burden.
- MeSH
- cholesterol krev MeSH
- dospělí MeSH
- HDL-cholesterol * krev MeSH
- kohortové studie MeSH
- LDL-cholesterol krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- magnetická rezonanční tomografie * MeSH
- mozek * diagnostické zobrazování patologie MeSH
- průřezové studie MeSH
- roztroušená skleróza * diagnostické zobrazování krev patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
AIMS: Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue. METHODS: We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF). RESULTS: We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels. CONCLUSIONS: Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.
- MeSH
- alfa-synuklein * metabolismus MeSH
- biologické markery metabolismus MeSH
- chaperon endoplazmatického retikula BiP * metabolismus MeSH
- demence s Lewyho tělísky * patologie metabolismus MeSH
- eukaryotický iniciační faktor 2 * metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mozek metabolismus patologie MeSH
- neurotrofní faktory metabolismus MeSH
- proteiny tepelného šoku * metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- signální dráha UPR * fyziologie MeSH
- stres endoplazmatického retikula fyziologie MeSH
- upregulace * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: Microstructural characterization of patients with multiple sclerosis (MS) has been shown to correlate better with disability compared to conventional radiological biomarkers. Quantitative MRI provides effective means to characterize microstructural brain tissue changes both in lesions and normal-appearing brain tissue. However, the impact of the location of microstructural alterations in terms of neuronal pathways has not been thoroughly explored so far. Here, we study the extent and the location of tissue changes probed using quantitative MRI along white matter (WM) tracts extracted from a connectivity atlas. METHODS: We quantified voxel-wise T1 tissue alterations compared to normative values in a cohort of 99 MS patients. For each WM tract, we extracted metrics reflecting tissue alterations both in lesions and normal-appearing WM and correlated these with cross-sectional disability and disability evolution after 2 years. RESULTS: In early MS patients, T1 alterations in normal-appearing WM correlated better with disability evolution compared to cross-sectional disability. Further, the presence of lesions in supratentorial tracts was more strongly associated with cross-sectional disability, while microstructural alterations in infratentorial pathways yielded higher correlations with disability evolution. In progressive patients, all major WM pathways contributed similarly to explaining disability, and correlations with disability evolution were generally poor. CONCLUSIONS: We showed that microstructural changes evaluated in specific WM pathways contribute to explaining future disability in early MS, hence highlighting the potential of tract-wise analyses in monitoring disease progression. Further, the proposed technique allows to estimate WM tract-specific microstructural characteristics in clinically compatible acquisition times, without the need for advanced diffusion imaging.
- MeSH
- bílá hmota * diagnostické zobrazování patologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- mozek diagnostické zobrazování patologie MeSH
- průřezové studie MeSH
- roztroušená skleróza * diagnostické zobrazování patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
