Impact of white matter hyperintensities on structural connectivity and cognition in cognitively intact ADNI participants.

We used indirect brain mapping with virtual lesion tractography to test the hypothesis that the extent of white matter tract disconnection due to white matter hyperintensities (WMH) is associated with corresponding tract-specific cognitive performance decrements. To estimate tract disconnection, WMH masks were extracted from FLAIR MRI data of 481 cognitively intact participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used as regions of avoidance for fiber tracking in diffusion MRI data from 50 healthy young participants from the Human Connectome Project. Estimated tract disconnection in the right inferior fronto-occipital fasciculus, right frontal aslant tract, and right superior longitudinal fasciculus mediated the effects of WMH volume on executive function. Estimated tract disconnection in the left uncinate fasciculus mediated the effects of WMH volume on memory and in the right frontal aslant tract on language. In a subset of ADNI control participants with amyloid data, positive status increased the probability of periventricular WMH and moderated the relationship between WMH burden and tract disconnection in executive function performance.

Young versus older subject diffusion magnetic resonance imaging data for virtual white matter lesion tractography.

White matter hyperintensity (WMH) lesions on T2 fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and changes in adjacent normal-appearing white matter can disrupt computerized tract reconstruction and result in inaccurate measures of structural brain connectivity. The virtual lesion approach provides an alternative strategy for estimating structural connectivity changes due to WMH. To assess the impact of using young versus older subject diffusion MRI data for virtual lesion tractography, we leveraged recently available diffusion MRI data from the Human Connectome Project (HCP) Lifespan database. Neuroimaging data from 50 healthy young (39.2 ± 1.6 years) and 46 healthy older (74.2 ± 2.5 years) subjects were obtained from the publicly available HCP-Aging database. Three WMH masks with low, moderate, and high lesion burdens were extracted from the WMH lesion frequency map of locally acquired FLAIR MRI data. Deterministic tractography was conducted to extract streamlines in 21 WM bundles with and without the WMH masks as regions of avoidance in both young and older cohorts. For intact tractography without virtual lesion masks, 7 out of 21 WM pathways showed a significantly lower number of streamlines in older subjects compared to young subjects. A decrease in streamline count with higher native lesion burden was found in corpus callosum, corticostriatal tract, and fornix pathways. Comparable percentages of affected streamlines were obtained in young and older groups with virtual lesion tractography using the three WMH lesion masks of increasing severity. We conclude that using normative diffusion MRI data from young subjects for virtual lesion tractography of WMH is, in most cases, preferable to using age-matched normative data.

Associations of phosphorylated tau pathology with whole-hemisphere ex vivo morphometry in 7 tesla MRI.

INTRODUCTION: Neurodegenerative disorders are associated with different pathologies that often co-occur but cannot be measured specifically with in vivo methods. METHODS: Thirty-three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2-weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere. RESULTS: Partial Spearman correlation of phosphorylated tau and cortical thickness with TAR DNA-binding protein 43 (TDP-43) and α-synuclein scores, age, sex, and postmortem interval as covariates showed significant relationships in entorhinal and primary visual cortices, temporal pole, and insular and posterior cingulate gyri. Linear models including Braak stages, TDP-43 and α-synuclein scores, age, sex, and postmortem interval showed significant correlation between Braak stage and thickness in the parahippocampal gyrus, entorhinal cortex, and Broadman area 35. CONCLUSION: We demonstrated an association of measures of AD pathology with tissue loss in several AD regions despite a limited range of pathology in these cases. HIGHLIGHTS: Neurodegenerative disorders are associated with co-occurring pathologies that cannot be measured specifically with in vivo methods. Identification of the topographic patterns of these pathologies in structural magnetic resonance imaging (MRI) may provide probabilistic biomarkers. We demonstrated the correlation of the specific patterns of tissue loss from ex vivo brain MRI with underlying pathologies detected in postmortem brain hemispheres in patients with Alzheimer's disease (AD) spectrum disorders. The results provide insight into the interpretation of in vivo structural MRI studies in patients with AD spectrum disorders.

Multi-Center Repeatability of Macular Capillary Perfusion Density Using Optical Coherence Tomography Angiography.

Background/Aims: This study was to determine the test-retest repeatability in quantifying macular capillary perfusion density (CPD, expressed as fractal dimension) using optical coherence tomography angiography (OCTA) in a multi-center setting. Methods: OCTA data were obtained in self-reported healthy subjects from Bascom Palmer Eye Institute at the University of Miami (UM, N = 18) and the University of Pennsylvania (UPenn, N = 22). The right eye of each subject was imaged twice at the first visit and then again at an interval of one week to assess intra-visit and inter-visit repeatability. The macular area of the OCTA-derived capillary perfusion density (OCTA-CPD) was analyzed by custom-made image processing and fractal analysis software. Fractal analysis was performed on the skeletonized microvascular network to yield OCTA-CPD by box-counting to the fractal dimension (Dbox) in the superficial vascular plexus (SVP). Repeatability was assessed by three measures: within-subject standard deviation (Sw), coefficient of variation (CoV) of repeated measures, and intraclass correlation coefficient (ICC). Results: OCTA-CPD from both sites (UM and UPENN) showed good to excellent intra-visit repeatability, as demonstrated by the Sw ≤0.004, CoVs ≤0.23%, and ICCs ≥0.61. Similarly, both sites had good to excellent inter-visit repeatability, as shown by the Sw ≤0.005, CoVs ≤0.28%, and ICCs ≥0.61. The Bland-Altman plots of the intra-visit and inter-visit measurements showed excellent agreements between the paired measurements with minimal biases. Conclusion: Our data showed that comparable high repeatability of OCTA-CPD can be achieved in both research sites using the same device, scan protocol, and image analysis.

Surgical complications of endoscopic approach to skull base: analysis of 584 consecutive patients.

PURPOSE: Endoscopic techniques have been widely applied for challenging cranial base surgeries in recent years. In this study, we evaluated the safety and efficacy of using the endoscopic endo-nasal route for various skull base pathologies in terms of postoperative complications. METHODS: A total of 584 consecutive patients who underwent endoscopic skull base surgery were studied. Peri- and post-operative complications and risk factors affecting the occurrence of these complications were evaluated. RESULTS: 648 endoscopic skull base surgical procedures were performed on 584 patients (47.8% females and 52.2% males) with the mean age of 41.2 years. Pituitary adenoma (69.3%) was the most common pathology. Post-operative mortality was 2.0%. The rates of post-operative permanent neurological deficit (one case of 6th nerve injury, two 12th nerve injuries and one hemiparesis) and visual deterioration were 0.6% and 1.5%, respectively. Ten patients (1.7%) were complicated with meningitis and it was the cause of death in 3. Systemic complications not directly attributable to skull base surgical access occurred in 2% (11 patients) with 5 mortalities. The rate of intra-operative vascular injury was 1% and among them one patient died due to PCA injury. The most common post-operative complications were diabetes insipidus (12.5%), anterior pituitary dysfunction (10.6%) and CSF leak (3.6%), respectively. In general, reoperation, malignant lesions, and level IV of surgical complexity were associated with a higher incidence of complications. CONCLUSION: Endoscopic endo-nasal approach can be a safe and less-morbid first-line treatment of patients with various skull base lesions.

Molecular Detection of Epstein-Barr Virus, Human Herpes Virus 6, Cytomegalovirus, and Hepatitis B Virus in Patients with Multiple Sclerosis.

BACKGROUND Multiple sclerosis (MS) is a chronic disease with significant morbidity. A wide spectrum of risk factors has been suggested that triggers the development of MS. Among them, several viral infections have been implicated to play a role in MS pathogenesis. We aimed to evaluate the relationship between viral diseases, including Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), cytomegalovirus (CMV), and hepatitis B virus (HBV) and MS in the present case-control study. METHODS About 100 patients with confirmed MS and age- and sex-matched individuals were selected as case and control groups, respectively. The patients were randomly selected from individuals diagnosed by neurologists based on the clinical signs and symptoms and imaging procedures. RESULTS More than 100 patients with MS and patients who were referred for other causes were analyzed for the presence of DNA of EBV, HHV6, CMV, and HBV separately. 9.37% of the control group had a positive test for the DNA of EBV in a real-time polymerase chain reaction (PCR), while the frequency of positive test result was zero in the case group (p = 0.0012). HBV DNA was not detected in both the case and control groups. The prevalence of CMV was 0.88 and zero in the control and case groups, respectively (p = 0.3410). For HHV6, 9.73 % of the control group had a positive result, while this test was positive in 5.88% of the patients with MS (p = 0.2959). CONCLUSION We detected a significantly higher number of individuals with DNA of EBV in their blood among the control group compared with the case group. In conclusion, the results suggest a surprisingly adverse association between MS and EBV, and no association was found between the presence of DNA of HBV, CMV, and HHV6 and MS.

Surgical Outcome of Endoscopic Endonasal Surgery of Large and Giant Pituitary Adenomas: An Institutional Experience from the Middle East.

OBJECTIVE: Surgical treatment of large and giant pituitary adenomas is challenging and associated with higher risk of complications and lower rate of gross total resection. We present our experience with surgical management of large and giant adenomas using the extended endoscopic transsphenoidal approach (EETA). METHODS: A total of 80 patients with large (30-39 mm) and giant (≥40 mm) pituitary adenomas who underwent tumor resection using EETA were studied. Radiologic data, hormonal and visual status, surgical outcomes, complications, and factors affecting the extent of resection were evaluated. RESULTS: Forty-five tumors (56.3%) were classified as large and 35 (43.8%) as giant adenomas. Gross total resection was achieved in 66 patients (82.5%), near-total resection in 10 (12.5%), and subtotal resection in 4 (5%). Preoperative factors including larger tumor size, multilobular shape of tumor, and higher Knosp scores significantly decrease the likelihood of gross total resection. Of patients with preoperative visual acuity impairment and visual field deficit, 76.8% and 74.1%, respectively, experienced improvement after surgery. The most common complications include new pituitary insufficiency (16.4%), permanent diabetes insipidus (7.5%), and cerebrospinal fluid leakage (5%). Two cases of meningitis (2.5%) and 3 deaths (3.8%) occurred in this cohort of patients. Mean follow-up duration was 24.2 months. CONCLUSIONS: EETA can be a safe and efficient approach as the first-line treatment of patients with large and giant pituitary adenomas and is associated with high rates of gross total resection or near-total resection, visual function improvement, and a relatively low rate of complications.

Convergent effects of a functional C3 variant on brain atrophy, demyelination, and cognitive impairment in multiple sclerosis.

BACKGROUND: Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity. OBJECTIVES: To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures. METHODS: In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) ≤ 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy ( n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90). RESULTS: While rs2230199 minor-allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance ( p = 0.02), lower brain parenchymal fraction ( p = 0.003), and higher lesion burden ( p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele. CONCLUSION: C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS.

Characterization of CD4+ and CD8+ T Cell Subsets and Interferon Regulatory Factor 4 (IRF4) in MS Patients Treated with Fingolimod (FTY-720): A Follow-up Study.

Fingolimod is a novel immunomodulatory drug used in patients with relapsing multiple sclerosis (MS) which reversibly inhibits egress of lymphocytes from lymph nodes. In this longitudinal study, the frequency of Interferon- gamma (IFN-γ)+, IL4+, IL17+ and IL10+ CD4+ and CD8+ T cell subsets were measured in Fingolimod treated patients before and after 12 months'(12M) therapy using flow cytometry and compared to those of naive, Betaferon treated MS patients and healthy individuals. Additionally, the level of transcription factor IRF4 and IL-6, IL-23, TGF-ß1 cytokines, required for differentiation of IL-17+ T cells, were assessed by RT-PCR and ELISA, respectively. In Fingolimod treated MS patients, we observed a significant decrease in the percentage of IFN-γ+/IL17+ CD4+ and CD8+ T cell subsets. In contrast, Fingolimod increased IL10+ CD4+ T cells. We also showed that IFN-γ+IL17+ co-producing CD8+ T cells were reduced in patients under fingolimod therapy. furthermore, Fingolimod could reduce the expression level of IRF4 in patients while IL6 was increased in the supernatant of cultured peripheral blood mononuclear cells. Our data showed that Fingolimod treatment alters CD4+ and CD8+ T cell subsets and reduces expression of IRF-4, which affects the proportion of pathogenic memory T cells in peripheral blood.

Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis.

OBJECTIVE: To determine the motor-behavioral and neural correlates of putative functional common variants in the sodium-channel NaV1.8 encoding gene (SCN10A) in vivo in patients with multiple sclerosis (MS). METHODS: We recruited 161 patients with relapsing-onset MS and 94 demographically comparable healthy participants. All patients with MS underwent structural MRI and clinical examinations (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite [MSFC]). Whole-brain voxel-wise and cerebellar volumetry were performed to assess differences in regional brain volumes between genotype groups. Resting-state fMRI was acquired from 62 patients with MS to evaluate differences in cerebellar functional connectivity. All participants were genotyped for 4 potentially functional SCN10A polymorphisms. RESULTS: Two SCN10A polymorphisms in high linkage disequilibrium (r(2) = 0.95) showed significant association with MSFC performance in patients with MS (rs6795970: p = 6.2 × 10(-4); rs6801957: p = 0.0025). Patients with MS with rs6795970(AA) genotype performed significantly worse than rs6795970(G) carriers in MSFC (p = 1.8 × 10(-4)) and all of its subscores. This association was independent of EDSS and cerebellar atrophy. Although the genotype groups showed no difference in regional brain volumes, rs6795970(AA) carriers demonstrated significantly diminished cerebellar functional connectivity with the thalami and midbrain. No significant SCN10A-genotype effect was observed on MSFC performance in healthy participants. CONCLUSIONS: Our data suggest that SCN10A variation substantially influences functional status, including prominent effects on motor coordination in patients with MS. These findings were supported by the effects of this variant on a neural system important for motor coordination, namely cerebello-thalamic circuitry. Overall, our findings add to the emerging evidence that suggests that sodium channel NaV1.8 could serve as a target for future drug-based interventions to treat cerebellar dysfunction in MS.

Genome-wide variant by serum urate interaction in Parkinson's disease.

OBJECTIVE: Serum urate levels have been associated with risk for and progression of Parkinson's disease (PD). Urate-related compounds are therapeutic candidates in neuroprotective efforts to slow PD progression. A urate-elevating agent is currently under investigation as a potential disease-modifying strategy in people with PD. However, PD is a heterogeneous disorder, and genetic variation may explain divergence in disease severity and progression. METHODS: We conducted a genome-wide association study to identify gene variant × serum urate interaction effects on the striatal (123) I-ioflupane (DaTscan) binding ratio measured using single photon emission computed tomography in patients with possible PD from the Parkinson's Progression Markers Initiative (PPMI, n = 360). Follow-up analyses were conducted to assess gene variant × serum urate interaction effects on magnetic resonance imaging-derived regional brain volumes and clinical status. We then attempted to replicate our primary analysis in patients who entered the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) with a clinical diagnosis of PD (n = 349). RESULTS: Rs1109303 (T>G) variant within the INPP5K gene on chromosome 17p13.3 demonstrated a genome-wide significant interaction with serum urate level to predict striatal dopamine transporter density among all PPMI participants (n = 359) with possible PD (p = 2.01 × 10(-8) ; after excluding participants with SWEDD [scan without evidence of dopaminergic deficit]: p = 1.12 × 10(-9) ; n = 316). Independent of striatal dopamine transporter density, similar effects on brain atrophy, bradykinesia, anxiety, and depression were observed. No effect was present in the PRECEPT sample at baseline; however, in non-SWEDD PD participants in PRECEPT (n = 309), we observed a significant longitudinal genotype × serum urate interaction effect, consistent in direction with the PPMI sample, on progression of striatal dopamine transporter density over the 22-month follow-up. INTERPRETATION: Genetic profile combined with serum urate level can be used to predict disease severity and potential disease progression in patients with PD. These results may be relevant to therapeutic efforts targeting the urate pathway.

A further TWEAK to multiple sclerosis pathophysiology.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF super family that controls many cellular activities including proliferation, migration, differentiation, apoptosis, and inflammation by binding to fibroblast growth factor-inducible 14 (Fn14), a highly inducible cell surface receptor. Recent studies have indicated that TWEAK-Fn14 axis signaling may contribute to chronic autoimmune diseases. TWEAK expression via microglia in cortical lesions, presence of TWEAK(+) macrophages in inflamed leptomeninges, and absence of TWEAK/Fn14 expression in healthy brain implicates importance of this pathway in pathogenesis of multiple sclerosis lesions. TWEAK-Fn14 axis blockade has also shown promise in various multiple sclerosis animal models. Stimulation of the TWEAK/Fn14 pathway can result in activation of both canonical and noncanonical NF-κB signaling and could also stimulate mitogen-activated protein kinase (MAPK) signaling pathways. Here, we have reviewed evidence of the possible role of TWEAK-Fn14 axis in pathophysiology of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) via neuroinflammation, tissue remodeling, blood-brain barrier (BBB) disruption, neurodegeneration, and astrogliosis.