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Small vessel disease (SVD) is a disorder that causes vascular lesions in the entire parenchyma of the human brain. At present, it is not well understood how primary and secondary damage interact to give rise to the complex scenario of white matter (WM) and grey matter (GM) lesions. Using novel cross-sectional and longitudinal connectomic approaches, we unveil the bidirectional nature of GM and WM changes, that is, primary cortical neurodegeneration that leads to secondary alterations in vascular border zones, and WM lesions that lead to secondary neurodegeneration in cortical projecting areas. We found this GM-WM interaction to be essential for executive cognitive performance. Moreover, we also observed that the interlocked degeneration of GM and WM over time associates with prototypical expression levels of genes potentially linked to SVD. Among these connectomic-genetic intersections, we found that the Androgen Receptor (AR) gene, is a particularly central candidate gene that might confer key vulnerability for brain lesion development in SVD. In conclusion, this study advances in the understanding of the bidirectional relationships between GM and WM lesions, primary and secondary vascular neurodegeneration, and sheds light on the genetic signatures of SVD. © 2022 The Authors

Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-beta and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, C-11-Pittsburgh compound-B-PET, F-18-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-beta, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-beta, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-beta, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-beta and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-beta, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.

We give a partition of the critical strip, associated with each partial sum 1 + 2 𝑧 + ⋯ + 𝑛 𝑧 of the Riemann zeta function for Re 𝑧 < − 1 , formed by infinitely many rectangles for which a formula allows us to count the number of its zeros inside each of them with an error, at most, of two zeros. A generalization of this formula is also given to a large class of almost-periodic functions with bounded spectrum.

The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Among other applications, FD has been used to identify abnormalities of the human brain in conventional magnetic resonance imaging (MRI), including white matter abnormalities in patients with Multiple Sclerosis (MS). Extensive grey matter (GM) pathology has been recently identified in MS and it appears to be a key factor in long-term disability. The aim of the present work was to assess whether FD measurement of GM in T1 MRI sequences can identify GM abnormalities in patients with MS in the early phase of the disease. A voxel-based morphometry approach optimized for MS was used to obtain the segmented brain, where we later calculated the three-dimensional FD of the GM in MS patients and healthy controls.We found that patients with MS had a significant increase in the FD of the GM compared to controls. Such differences were present even in patients with short disease durations, including patients with first attacks of MS. In addition, the FD of the GM correlated with T1 and T2 lesion load, but not with GM atrophy or disability. The FD abnormalities of the GM here detected differed from the previously published FD of the white matter in MS, suggesting that different pathological processes were taking place in each structure. These results indicate that GM morphology is abnormal in patients with MS and that this alteration appears early in the course of the disease.

T regulatory cells type 1 (Tr1 cells) are excellent candidates for cell therapy in multiple sclerosis (MS). The aim of our study was to assess the functional state of Tr1 cells and IL-10R signaling in patients with MS. Tr1 cells were induced in vitro by activation with anti-CD46 antibodies in controls and patients with MS. Cells were phenotyped by cytometry and suppression assays, and the expression of cytokines and transcription factors was evaluated by real-time PCR, ELISA, cytometry and Western blotting. We found that the activity of Tr1 cells and IL-10R signaling is impaired in MS patients since Tr1 cells isolated from MS patients produced less IL-10 than those obtained from controls. Indeed, the supernatants from Tr1 cells from controls did not suppress the proliferation of stimulated CD4(+) cells from patients with MS. Furthermore, the IL-10R signaling pathway was not fully active in CD4(+) cells from MS patients and these cells had higher baseline levels of SOCS3 transcripts than controls. Indeed, after in vitro IL-10 stimulation, the expression levels of the STAT1, STAT3 and IL-10RA genes were higher in MS patients than in controls. Moreover, Stat-3 phosphorylation was lower in controls than in patients after IL-10 stimulation. These results indicate that IL-10 regulatory function is impaired in patients with MS.

Background: The MSdiag™ test assess a set of 34 circulating antibodies directed against fatty acids, acetylcholine-like, azelaic acid, malondialdehyde residue, NO-modified amino-acids and enterobacterial antigens by ELISA (M Geffard. J Neuroimmunol 1996). These set of antibodies have been described to be differentially expressed in different MS disease course. Objective: To assess the association between MSdiag™ test and disease activity in a cohort of MS patients. Methods: We study a cohort of 61 MS patients with early to medium disease duration (22 CIS, 28 RRMS, 5 SPMS, 6 PPMS), low-medium disability (EDSS: 2.0 (0 – 7.0); MSSS: 4.6; MSFC: 0.64 +1.68) and a relapse rate in the 2 previous years of 1.43. Patients were followed every 3 months for 2 years. The MSdiag test was performed every 3 months in a blind manner. A 3D MRI with gadolinium study was performed at baseline. Results: Two patients were lost for follow-up. Relapse rate during the follow-up was 1.23, and 26 patients were relapse-free. The increase in the EDSS by the end of the study was 0.41 + 0.7 and 12 patients had confirmed progression (1 point increase in the EDSS confirmed at 6 months). Twelve CIS patients converted to RRMS and 5 RRMS patients developed SPMS. We found moderate correlation between MSdiag™ subtest directed against enterobaterial antigens and disability (EDSS and MSFC) at the end of the study: 1) the rise of antibodies 5M, 16M, 12M, 19M and 5A was associated with disease progression; 2) we found a moderate correlation between 16M and 5M antibody titers and EDSS change (confirmed at 6 months). The rise of antibody 16M was associated with the conversion from CIS to RRMS; and the increase of antibody 17A titers was associated with being non relapse-free by the end of the study. None of the tests correlated with the number of relapses in the follow-up, disease subtype at baseline, response to immunomodulatory therapy or gadolinium enhancing lesions. Conclusions: The assessment of several antibodies in the MSdiag™ test might be useful to identify patients with active disease