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Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10–7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

Purpose Noninvasive methods are desired to predict the treatment response to Stereotactic Radiosurgery (SRS) to improve individual tumor management. In a previous study, we demonstrated that Diffusion Tensor Imaging (DTI)-derived parameter maps significantly correlate to SRS response. This study aimed to analyze and compare the predictive value of intratumoral ADC and DTI parameters in patients with meningiomas undergoing radiosurgery. Methods MR images of 70 patients treated with Gamma Knife SRS for WHO grade I meningiomas were retrospectively reviewed. MR acquisition included pre- and post-treatment DWI and DTI sequences, and subtractions were calculated to assess for radiation-induced changes in the parameter values. Results After a mean follow-up period (FUP) of 52.7 months, 69 of 70 meningiomas were controlled, with a mean volume reduction of 34.9%. Whereas fractional anisotropy (FA) values of the initial exam showed the highest correlation to tumor volume change at the last FU (CC=-0.607), followed by the differences between first and second FU values of FA (CC=-0.404) and the first longitudinal diffusivity (LD) value (CC=-0.375), the correlation coefficients of all ADC values were comparably low. Nevertheless, all these correlations, except for ADC measured at the first follow-up, reached significance. Conclusion For the first time, the prognostic value of ADC maps measured in meningiomas before and at first follow-up after Gamma Knife SRS, was compared to simultaneously acquired DTI parameter maps. Quantities assessed from ADC maps present significant correlations to the volumetric meningioma response but are less effective than correlations with DTI parameters.

Purpose:This report presents the first investigation of the radiomics value in predicting the meningioma volumetric response to gamma knife radiosurgery (GKRS). Methods:The retrospective study included 93 meningioma patients imaged by three Tesla MRI. Tumor morphology was quantified by calculating 337 shape, first- and second-order radiomic features from MRI obtained before GKRS. Analysis was performed on original 3D MR images and after their laplacian of gaussian (LoG), logarithm and exponential filtering. The prediction performance was evaluated by Pearson correlation, linear regression and ROC analysis, with meningioma volume change per month as the outcome. Results:Sixty calculated features significantly correlated with the outcome. The feature selection based on LASSO and multivariate regression started from all available 337 radiomic and 12 non-radiomic features. It selected LoG-sigma-1-0-mm-3D_firstorder_InterquartileRange and logarithm_ngtdm_Busyness as the predictively most robust and non-redundant features. The radiomic score based on these two features produced an AUC = 0.81. Adding the non-radiomic karnofsky performance status (KPS) to the score has increased the AUC to 0.88. Low values of the radiomic score defined a homogeneous subgroup of 50 patients with consistent absence (0%) of tumor progression. Conclusion:This is the first report of a strong association between MRI radiomic features and volumetric meningioma response to radiosurgery. The clinical importance of the early and reliable prediction of meningioma responsiveness to radiosurgery is based on its potential to aid individualized therapy decision making.

ImportanceCerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited.ObjectiveTo assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity.Design, Setting, and ParticipantsIn this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023.Main Outcomes and MeasuresMain outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests.ExposuresExposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index.ResultsThis study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD.Conclusions and RelevanceIn this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

To examine structural connectivity of white matter tracts in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) dystonia and identify those ones which correlate negatively to severity of symptoms.In a group of 41 patients suffering from PKAN dystonia and an age- and gender-matched control group, white matter tractography was carried out, based on diffusion tensor imaging magnetic resonance data. Postprocessing included assessment of Quantitative Anisotropy (QA) using q-space diffeomorphic reconstruction in order to reduce influence of iron accumulation in globus pallidus of patients.Whole brain tractography presented significantly reduced QA values in patients (0.282 ± 0.056, as compared to controls (0.325 ± 0.046, p 0.001). 9 fiber clusters of tracts correlated negatively to the dystonia score of patients: the middle cerebellar peduncle and the tracts of both cerebellar hemispheres as well as corpus callosum, forceps minor, the superior cortico-striate tracts and the superior thalamic radiations of both cerebral hemispheres (False Discovery Rate FDR = 0.041).The finding of a reduced global structural connectivity within the white matter and of negative correlation of motor system-related tracts, mainly those between the basal ganglia, cortical areas and the cerebellum, fits well to the concept of a general functional disturbance of the motor system in PKAN.

Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology.We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers.Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort.GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.

Purpose To search for texture features of routine magnetic resonance imaging to predict tumor volume reduction and transient versus permanent tumor progression of vestibular schwannomas treated by Gamma Knife stereotactic radiosurgery. Materials and Methods Included were 23 patients with vestibular schwannomas treated in our center and followed over a period of 23.7–80.3 months (mean 42.7). Magnetic resonance imaging was performed on a 3-Tesla scanner and included T1-weighted images with and without contrast enhancement, T2-weighted, and fluid-attenuated inversion recovery images. Volumetric results were followed longitudinally over time and correlated to texture features as mean, minimum, maximum, standard deviation, skewness, and kurtosis of normalized signals taken from regions of interest covering the total tumor volume. Results In total, 14 tumors showed early progression during the first 5–18 months (2 cases permanent, 12 cases transient), whereas 9 tumors regressed immediately after SRS. Kurtosis of T2-weighted image intensity values turned out to predict progression best with a sensitivity and specificity of 71% and 78%. From all texture feature parameters, only the minimum of the normalized T2-weighted image intensity values correlated significantly to the final reduction of tumor volume per month (correlation coefficient = −0.634, P Conclusions Texture feature analysis helps to predict permanent versus transient enlargement and final volume reduction of schwannomas after SRS. Thus, alternative treatment strategies might be considered, mainly in large tumors, where further clinical deterioration cannot be excluded. To confirm these results, a prospective study including more cases and a longer follow-up period is necessary.

Hypofractionation has been recently considered as an alternative to improve stereotactic radiosurgery treatments of lesions close to the optic pathways. To estimate the intrinsic benefit from fractionation versus single-dose radiosurgery for perioptic lesions, the value of the alpha/beta ratio of the optic pathways needs to be known. Based on the linear quadratic (LQ) model, hypofractionation versus single-fraction SRS can be justified in cases where parts of the optic apparatus necessarily receive the full therapeutic peripheral dose, if there is a positive difference between α/s of the lesion and the α/s of the surrounding organs at risk. Furthermore, the knowledge of α/s ratios is required to calculate radiobiological dose parameters, such as the biologically effective dose (BED) and single fraction equivalent dose (SFED), and helps estimate normal tissue complication probability (NTCP), dose constraints, and retreatment doses. Only 3 alpha/beta ratios for the visual system have been published so far, varying between -0.6 and 3.06 Gy. The alpha/beta ratio of the optic pathways was estimated from a fraction equivalent plot based on a meta-analysis of 429 studies published between 2000 and June 2018. We included 15 studies with fraction sizes between 1 and 31, considering the following inclusion criteria: at least one well-documented RION case with detailed dosimetric analysis for the visual system, follow-up period (FUP) of at least 24 months, no tumor progression, no prior radiation. Additionally, we included results from our center on 68 hypofractionated treatments and 161 single-fraction SRS treatments for perioptic lesions. The fraction equivalent (FE) plot method revealed an alpha/beta ratio of the optic pathway of 1.03 Gy, confidence interval [-0.38–1.60]. Well-documented RION cases are rare in the literature; there is still not enough data to distinguish between alpha/beta ratios of the optic chiasm, the nerves, and the tracts. Optimized hypofractionation schedules were calculated for the treatment of meningiomas, chordomas, and brain metastases. Compared to single-fraction SRS, a significant intrinsic benefit from hypofractionation can be achieved, not only for perioptic malignant tumors, but for benign lesions as well, because of the very low alpha/beta ratio of the optic system of 1.03 Gy. An increased single fraction equivalent dose of up to 10% for perioptic meningiomas and of more than 25% for malignant tumors can be reached with optimized hypofractionated stereotactic radiosurgery schedules.

To demonstrate that lesions of the visual pathways due to suprasellar tumors are accompanied by alterations of the visual cortex and to see if these alterations are reversible after treatment of tumors by gamma knife radiosurgery. In 36 patients with peri-optic tumors and defects of their visual fields and in an age-matched control group, magnetic resonance imaging was performed before and after treatment. T1 weighted images were evaluated by voxel-based morphometry and correlated to the degree of visual field defects. In patients, grey matter density and cortical thickness were reduced in all parts of the occipital cortex, reaching significance (p

OBJECTIVEThe goal of this study was to identify parameters from routine T1- and T2-weighted MR sequences and diffusion tensor imaging (DTI) that best predict the volumetric changes in a meningioma after treatment with Gamma Knife radiosurgery (GKRS).METHODSIn 32 patients with meningioma, routine MRI and DTI data were measured before GKRS. A total of 78 parameters derived from first-level texture analysis of the pretreatment MR images, including calculation of the mean, SD, 2.5th and 97.5th percentiles, and kurtosis and skewness of data in histograms on a voxel-wise basis, were correlated with lesion volume change after a mean follow-up period of 3 years (range 19.5–63.3 months).RESULTSSeveral DTI-derived parameters correlated significantly with a meningioma volume change. The parameter that best predicted the results of GKRS was the 2.5th percentile value of the smallest eigenvalue (L3) of the diffusion tensor (correlation coefficient 0.739, p ≤ 0.001), whereas among the non-DTI parameters, only the SD of T2-weighted images correlated significantly with a tumor volume change (correlation coefficient 0.505, p ≤ 0.05, after correction for family-wise errors using false-detection-rate correction).CONCLUSIONSDTI-derived data had a higher correlation to shrinkage of meningioma volume after GKRS than data from T1- and T2-weighted image sequences. However, if only routine MR images are available, the SD of T2-weighted images can be used to predict control or possible progression of a meningioma after GKRS.

OBJECTIVEDiffusion tensor imaging (DTI) parameters are able to differentiate between meningioma subtypes. The hypothesis that there is a correlation between DTI parameters and the change in tumor size after Gamma Knife radiosurgery (GKRS) was analyzed.METHODSDTI parameters were measured using MRI before GKRS in 26 patients with meningiomas. The findings were correlated with the change in tumor size after treatment as measured at the last follow-up (range 12.5–45 months).RESULTSOnly those meningiomas that showed the highest fractional anisotropy (FA), the lowest spherical index of the tensor ellipsoid (Cs), and the lowest radial diffusivity (RD) either increased or remained stable in terms of volume, whereas all other meningiomas decreased in volume. The correlation between the DTI parameters (correlation values of −0.81 for FA, 0.75 for Cs, 0.66 for RD, and 0.66 for mean diffusivity) and the rate of volume change per month was significant (p ≤ 0.001). Other factors, including original tumor size, prescription dose, and patient age, did not correlate significantly.CONCLUSIONSMeningiomas that show high FA values—as well as low Cs, low RD, and low mean diffusivity values—do not respond as well to GKRS in comparison with meningiomas with low FA values. This finding might be due to their higher content level of fibrous tissue. In particular, the meningioma with the highest FA value (0.444) considerably increased in volume (by 32.3% after 37 months), whereas the meningioma with the lowest FA value (0.151) showed the highest rate of reduction (3.3% per month) in this study.

Background and Importance Transtegmental brain herniation into the petrous bone is a rare cause of rhinoliquorrhea. Our case presents a combination of several typical clinical and imaging findings illustrating the ongoing etiologic discussion of such cerebrospinal fluid (CSF) fistulas. Clinical Presentation A 53-year-old man presented with nasal discharge after a strong effort to suppress coughing. Imaging revealed a transtegmental herniation of parts of the inferior temporal gyrus into the petrous bone and in addition a combination of signs of chronically increased intracranial pressure and a hyperpneumatization of the petrous bone. The fistula was closed by a middle cranial fossa approach. Conclusion The case illustrates the two main predisposing factors for development of petrous bone CSF fistulas: increased intracranial pressure and thinning of the tegmental roof due to extensive development of air cells. Because the CSF leakage repair does not change the underlying cause, patients have to be informed about the possibility of developing increased intracranial pressure and recurrences of brain herniations at other sites.

To search for microstructural lesions of normal-appearing cerebral white matter surrounding a tumor or a vascular lesion, after single-fraction stereotactic Gamma Knife (GK) radiosurgery.In 43 patients with different brain lesions, magnetic resonance including diffusion tensor imaging (DTI) was performed before and after GK radiosurgery and change of parameters was measured in areas surrounding the lesion.Outside the lesion, there was an increase in mean diffusivity (MD) and radial diffusivity (RD) between 2.1% and 3.4% in the 15–10 Gy and in the 10–5 Gy perilesional isodose volumes, which reached statistical significance (pairedWe report some minor, but nevertheless significant changes in DTI parameters in normal-appearing perilesional brain tissue after GK radiosurgery progressing with time, which partially may be induced by the radiation itself and partially may be due to indirect effects of lesion reactions to the radiation. Follow-up studies are necessary for further characterization of these changes and assessment of their time course.

Background: Although intracranial Rosai–Dorfman disease is a principally benign lymphohistiocytosis, some patients run a relapsing or progressive course. However, reports about long-term follow-up are extremely rare. Case Description: In two patients, initial tumor resection was incomplete or followed by recurrences over 3 years, which finally subsided after application of chemotherapy, and patients remained tumor-free for more than 7 years thereafter. Conclusion: Up to now there is no agreement on how to treat complicated cases of intracranial Rosai–Dorfman disease; our good experience with adjuvant chemotherapy and long-term follow-up will contribute to treatment planning in complicated cases.

Background: Both genetic variants and epigenetic features contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as the hub of both the genetic and epigenetic effects, in Hispanics decedents and generalized the findings to Non-Hispanic Whites (NHW) decedents., Methods: First, we derived the dosage of the CpG site-creating allele of multiple CGSes in each 1 KB window across the genome and we conducted a sliding window association test with clinical diagnosis of AD in 7,155 Hispanics (3,194 cases and 3,961 controls) using generalized linear mixed models with the adjustment of age, sex, population structure, genomic relationship matrix, and genotyping batches. Next, using methylation and bulk RNA-sequencing data from the dorsolateral pre-frontal cortex in 150 Hispanics brains, we tested the cis- and trans-effects of AD associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we checked their enriched pathways., Results: We identified six genetic loci in Hispanics with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score=55.2, P= 4.06×10 -8 ), between VRTN (Score=-19.6, P= 1.47×10 -8 ) and SYNDIG1L (Score=-37.7, P= 2.25×10 -9 ), SPG7 (16q24.3) (Score=40.5, P= 2.23×10 -8 ), PVRL2 (Score=125.86, P= 1.64×10 -9 ), TOMM40 (Score=-18.58, P= 4.61×10 -8 ), and APOE (Score=75.12, P= 7.26×10 -26 ). CGSes in PVRL2 and APOE were also genome-wide significant in NHW. Except for ADAM20 , CGSes in all the other five loci were associated with Hispanic brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L ( P =0.08), brain methylation levels in all the other five loci affected downstream RNA expression in the Hispanics ( P <0.05), and methylation at VRTN and TOMM40 were also associated with RNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and synapse (FDR<0.05)., Conclusions: We identified six CpG associated genetic loci associated with AD in Hispanics, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.