Development Of Brain Atrophy Research Articles

Exploring the effects of extended interval dosing of natalizumab and drug concentrations on brain atrophy in multiple sclerosis.

Extended interval dosing (EID) of natalizumab treatment is increasingly used in multiple sclerosis. Besides the clear anti-inflammatory effect, natalizumab is considered to have neuroprotective properties as well. This study aimed to study the longitudinal effects of EID compared to standard interval dosing (SID) and natalizumab drug concentrations on brain atrophy. Patients receiving EID or SID of natalizumab with a minimum radiological follow-up of 2 years were included. Changes in brain atrophy measures over time were derived from clinical routine 3D-Fluid Attenuated Inversion Recovery (FLAIR)-weighted magnetic resonance imaging (MRI) scans using SynthSeg. We found no differences between EID (n = 32) and SID (n = 50) for whole brain (-0.21% vs -0.16%, p = 0.42), ventricular (1.84% vs 1.13%, p = 0.24), and thalamic (-0.32% vs -0.32%, p = 0.97) annualized volume change over a median follow-up of 3.2 years. No associations between natalizumab drug concentration and brain atrophy rate were found. We found no clear evidence that EID compared to SID or lower natalizumab drug concentrations have a negative impact on the development of brain atrophy over time.

Short-term brain atrophy evolution after initiation of immunotherapy in a real-world multiple sclerosis cohort.

In multiple sclerosis (MS), brain atrophy measurements have emerged as an important biomarker reflecting neurodegeneration and disability progression. However, due to several potential confounders, investigation of brain atrophy in clinical routine and even in controlled clinical studies can be challenging. The aim of this study was to investigate the short-term dynamics of brain atrophy development after initiation of disease-modifying therapy (DMT) in a "real-world setting." In this retrospective study, we included MS patients starting DMT (natalizumab, fingolimod, dimethyl fumarate, or interferon-ß1a) or without DMT, availability of a baseline MRI, and two annual follow-up scans on the same MRI system. Two-timepoint percentage brain volume changes (PBVCs) were calculated. Fifty-five MS patients (12 patients starting DMT with natalizumab, 7 fingolimod, 14 dimethyl fumarate, 11 interferon-ß1a, and 11 patients without DMT) were included. We found the highest PBVCs in the first 12 months after initiation of natalizumab treatment. Furthermore, the PBVCs in our study were very much comparable to the results observed by other groups, as well as for fingolimod, dimethyl fumarate, and interferon-ß1a. We found PBVCs that are comparable to the results of previous studies, suggesting that brain atrophy, assessed on 3D MRI data sets acquired on the same 3T MRI, provides a robust MS biomarker.

Dissecting the role of H-2D bclass I molecule in the development of brain atrophy during Theiler’s murine encephalomyelitis virus (TMEV) infection

Abstract Brain atrophy is a common feature of many neurological diseases as diverse as Alzheimer’s disease, cerebral palsy, Huntington’s disease, multiple sclerosis, epilepsy, encephalitis, neurosyphilis, neuroAIDS, and Covid-19 infection. We have developed a murine model of brain atrophy using the Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis. In this study, we investigated the contribution of the MHC class I molecule, H-2Db, in generating an immune response associated with the onset of brain atrophy using mice with a C57BL/6 background. The H-2D bClass I molecule not only contributed to significantly more ventricular enlargement in a T2-weighted MRI at 45 d.p.i., but this ventricular enlargement correlated to CD8 T cell infiltration. To further define the cellular and molecular mechanisms of MHC class I molecules in TMEV induced brain atrophy we investigated the cell specific contribution of brain resident antigen presenting cells (APCs) in ventricular atrophy. We developed novel bi-transgenic mouse lines with tamoxifen induced conditional ablation of the H-2Db class I molecule in Cx3CR1+ brain resident myeloid cells. Cx3CR1cre+/Db Lox P mice presented with significantly less ventricular atrophy at 45 d.p.i., compared to cre- littermates along with a decrease in CD8 T cell infiltration. These results strongly imply that antigen presentation by H-2Db on myeloid cells, at least in part is responsible for the development of brain atrophy and provided insight into the molecular mechanism of this poorly understood neuropathology. NS103212, NS122174

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Sclerostin, vascular risk factors, and brain atrophy in excessive drinkers.

Heavy alcohol consumption causes several organic complications, including vessel wall calcification. Vascular damage may be involved in the development of brain atrophy and cognitive impairment. Recently, sclerostin (whose levels may be altered in alcoholics) has emerged as a major vascular risk factor. The objective of the present study is to analyze the prevalence of vascular calcifications in alcoholics, and the relationships of these lesions with brain atrophy, as well as the role of sclerostin on these alterations. A total of 299 heavy drinkers and 32 controls were included. Patients underwent cranial computed tomography, and several indices related to brain atrophy were calculated. In addition, patients and controls underwent plain radiography and were evaluated for the presence or absence of vascular calcium deposits, cardiovascular risk factors, liver function, alcohol intake, serum sclerostin, and routine laboratory variables. A total of 145 (48.47%) patients showed vascular calcium deposits, a proportion significantly higher than that observed in controls (χ2 = 16.31; p < 0.001). Vascular calcium deposits were associated with age (t = 6.57; p < 0.001), hypertension (t = 5.49; p < 0.001), daily ethanol ingestion (Z = 2.18; p = 0.029), duration of alcohol consumption (Z = 3.03; p = 0.002), obesity (χ2 = 4.65; p = 0.031), total cholesterol (Z = 2.04; p = 0.041), triglycerides (Z = 2.05; p = 0.04), and sclerostin levels (Z = 2.64; p = 0.008). Calcium deposits were significantly related to Bifrontal index (Z = 2.20; p = 0.028) and Evans index (Z = 2.25; p = 0.025). Serum sclerostin levels were related to subcortical brain atrophy, assessed by cella media index (Z = 2.43; p = 0.015) and Huckmann index (ρ = 0.204; p = 0.024). Logistic regression analyses disclosed that sclerostin was the only variable independently related to brain atrophy assessed by altered cella media index. Sclerostin was also related to the presence of vascular calcifications, although this relationship was displaced by age if this variable was also included. Prevalence of vascular calcification in alcoholics is very high. Vascular calcium deposits are related to brain atrophy. Serum sclerostin is strongly related to brain shrinkage and also shows a significant relationship with vascular calcifications, only displaced by advanced age.

Dissecting the role of H-2Db class I molecule in the development of brain atrophy during Theiler’s murine encephalomyelitis virus (TMEV) infection

Abstract Brain atrophy is a common feature of many neurological diseases as diverse as Alzheimer’s disease, cerebral palsy, Huntington’s disease, Krabbe disease, multiple sclerosis, Pick’s disease, epilepsy, encephalitis, neurosyphilis, neuroAIDS, and Covid-19 infection. We have developed a murine model of brain atrophy using the Theiler’s murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis. In this study, we investigated the contribution of the MHC class I molecule, H-2Db, in generating an immune response associated with the onset of brain atrophy. To define the roll of the MHC class I molecule in the cellular and molecular mechanisms of brain atrophy, we developed a novel bi-transgenic mouse lines with tamoxifen induced conditional ablation of the H-2Db class I molecule in Cx3CR1+ brain resident myeloid cells on the C57BL/6 background. Interestingly, both CX3CR1cre/Db LoxP mice and their cre- littermate controls experienced short-term memory loss using novel object recognition tests. However, Cx3CR1cre+/Db LoxP mice presented with significantly less brain atrophy as assessed by analysis of lateral ventricular volume at 45 d.p.i. using T2-weighted MRI, compared to cre- littermates. This change in ventricular volume was sustained at 6 months post infection. These results strongly imply a requirement for antigen presentation by H-2Db on myeloid cells for the development of brain atrophy and provided insight into the molecular mechanism of this poorly understood neuropathology. Supported by NIH (RFI NS122174)

When cognitive impairment has a vascular origin.

When cognitive impairment has a vascular origin.

Association between homocysteine and third ventricle dilatation, mesencephalic area atrophy in Parkinson’s disease with cognitive impairment

ObjectivesThis study aimed to explore the association of homocysteine (Hcy) with third ventricle (V3) dilatation and mesencephalic area (MA) atrophy as determined by transcranial sonography (TCS) in Parkinson’s disease (PD) with cognitive impairment. MethodsThe final statistical analysis included 101 PD patients and 20 age- and sex-matched controls. Using the Movement Disorder Society (MDS) level II criteria for PD with cognitive impairment, we categorized the PD patients into PD with normal cognition group (PD) and PD with cognitive impairment group (PDC). All subjects underwent TCS and laboratory analysis. ResultsThe V3 width (r = 0.349, P = 0.005) and the MA (r = −0.484, P < 0.001) were significantly correlated with the Hcy concentration in the PDC patients. Binary logistic regression analysis revealed that age (OR [95% CI] = 1.114 [0.991–1.251], P = 0.002), and Hcy level (OR [95% CI] = 0.931 [0.752–1.153], P = 0.411) were independent risk factors for V3 dilatation. Hcy level (OR [95% CI] = 0.557 [0.323–0.967], P = 0.035) were independent risk factors for MA atrophy. After adjustment for confounding factors, the odds ratio of V3 dilatation was 3.50 (95% CI 1.054–11.399, P = 0.031) and the odds ratio of MA atrophy was 4.67 (95% CI 1.395–15.602, P = 0.012) in the patients with higher Hcy level compared with the lower level. ConclusionsThe results revealed a close association between the V3 width, MA and Hcy concentration in PD patients with cognitive impairment. We hypothesized that increased Hcy concentration played a significant role in the development of brain atrophy in PD with cognitive impairment.

Clinical-etiological and MRI parallels of encephalitis in children

Improving the diagnosis of encephalitis (EF) in children by establishing clinical, etiological and MRI parallels. 364 children aged from 1 month to 17 years with EF were examined. MRI of the brain and spinal cord, blood and CSF examination for herpes viruses type 1-6 (HHV), enteroviruses (EV), tick-borne encephalitis viruses (TBEV), Borrelia burgdorferi (BB), varicella zoster (VVZ), herpes simplex (HSV1) and Epstein-Barr (EBV) were performed. The etiological structure was dominated by HHV types 1-6, tick-borne infections (19%), EV (14.6%), and other agents (6%). Clinical and topical variants of EF: leukoencephalitis (leukoePH) - 68.4%, polyoencephalitis (polioePH) - 22.8% and panencephalitis (panePH) - 8.8%. LEUKOEPH was more often caused by VVZ, EBV and BB, foci in the white matter of the large hemispheres, sensitive, cerebellar and pyramidal symptoms, acute course followed by complete recovery (65.8%), the risk of exacerbations and progression with the development of multiple sclerosis in 6% were observed in 80.7%. POLIO in 71.1% were caused by TBEV or EV, lesions were located in the thalamus, basal ganglia, cortex, manifested by deep depression of consciousness, epilepsy, central paralysis and speech disorders, in 83.1% there was a chronic course with the development of brain atrophy. PanEF was caused by cytomegalovirus in more than 1/2 of cases, with subtotal-total white matter damage, in 1/3 of cases - with the involvement of other structures, there was a chronic course with polymorphism of neurological symptoms, rare complete recovery (15.6%). The cerebellar form of EF in 88.7% was associated with VZV, subcortical and stem - with TBEV and EV, cortical and limbic - with HSV-1 and 2 and HHV-6. The outcomes of EF depend both on the timeliness of etiological and neuroimaging diagnostics, and on the adequacy of early therapy already with EF, including the use of acyclovir in combination with recombinant interferons alpha-2-β with antioxidants, and the immediate appointment of Cytoflavin infusions upon admission to the hospital. Clinical and topical variants and forms of EF in children are associated with etiology, have different rates of complications, the nature of the course and outcomes, the knowledge of which makes it possible to optimize the diagnostic process.

Stroke promotes the development of brain atrophy and delayed cell death in hypertensive rats

Post-stroke cognitive impairment (PSCI) is a major source of disability, affecting up to two thirds of stroke survivors with no available therapeutic options. The condition remains understudied in preclinical models due to its delayed presentation. Although hypertension is a leading risk factor for dementia, how ischemic stroke contributes to this neurodegenerative condition is unknown. In this study, we used a model of hypertension to study the development of PSCI and its mechanisms. Spontaneously hypertensive rats (SHR) were compared to normotensive rats and were subjected to 1-h middle cerebral artery occlusion or sham surgery. Novel object recognition, passive avoidance test and Morris water maze were used to assess cognition. In addition, brain magnetic resonance images were obtained 12-weeks post-stroke and tissue was collected for immunohistochemistry and protein quantification. Stroked animals developed impairment in long-term memory at 4-weeks post-stroke despite recovery from motor deficits, with hypertensive animals showing some symptoms of anhedonia. Stroked SHRs displayed grey matter atrophy and had a two-fold increase in apoptosis in the ischemic borderzone and increased markers of inflammatory cell death and DNA damage at 12 weeks post-stroke. This indicates that preexisting hypertension exacerbates the development of secondary neurodegeneration after stroke beyond its acute effects on neurovascular injury.

Detection of Monocyte/Macrophage and Microglia Activation in the TMEV Model of Chronic Demyelination Using USPIO-Enhanced Ultrahigh-Field Imaging.

Blood-derived monocytes/macrophages can be labeled with ultrasmall superparamagnetic iron oxides (USPIO) at periphery and subsequently migrate into areas of inflammation in the brain. We investigated temporal pattern of migration of peripheral immune cells in Theiler's murine encephalomyelitis virus (TMEV) model of chronic demyelination by USPIO-enhanced imaging. Fifteen SJL mice (Envigo, Indianapolis, IN) were injected with TMEV (n = 12) or saline (n = 3) at 7 weeks of age. Brain MRI of 9.4 T was performed at 3 months postinfection (mpi) (the peak of inflammatory phase), at 4, 5, and 7 mpi (throughout neurodegenerative phase) using T2*-weighted gradient echo MRI, and performed 24 hours after USPIO injection. Contrast enhancing lesion (CEL) number and volume were measured and development of brain atrophy was assessed across serial time points. Clinical disability scale and rotarod score assessed disease progression. CEL was detected in a total of eight (66.7%) TMEV-infected animals and none of the Controls. The CEL was present in four (33.3%) TMEV-infected animals at 3 mpi, two (16.7%) at 4 mpi, six (54.5%) at 5 mpi, and four (44.4%) at 7 mpi, respectively. In TMEV-infected animals, the CEL number and volume increased significantly from 3 to 7 mpi (P < .01 for both). The correlation between total CEL number and volume with clinical and MRI outcomes was trending (P < .05). On histopathology analysis, CEL showed increased density of Iba1 staining for microglia activity. Serial USPIO imaging is a promising biomarker for investigating the effect of therapeutic interventions on monocytes/macrophages and microglia activation and neurodegeneration in TMEV-infected animals.

Disability Improvement Is Associated with Less Brain Atrophy Development in Multiple Sclerosis.

It is unknown whether deceleration of brain atrophy is associated with disability improvement in patients with MS. Our aim was to investigate whether patients with MS with disability improvement develop less brain atrophy compared with those who progress in disability or remain stable. We followed 980 patients with MS for a mean of 4.8 ± 2.4 years. Subjects were divided into 3 groups: progress in disability (n = 241, 24.6%), disability improvement (n = 101, 10.3%), and stable (n = 638, 65.1%) at follow-up. Disability improvement and progress in disability were defined on the basis of the Expanded Disability Status Scale score change using standardized guidelines. Stable was defined as nonoccurrence of progress in disability or disability improvement. Normalized whole-brain volume was calculated using SIENAX on 3D T1WI, whereas the lateral ventricle was measured using NeuroSTREAM on 2D-T2-FLAIR images. The percentage brain volume change and percentage lateral ventricle volume change were calculated using SIENA and NeuroSTREAM, respectively. Differences among groups were investigated using ANCOVA, adjusted for age at first MR imaging, race, T2 lesion volume, and corresponding baseline structural volume and the Expanded Disability Status Scale. At first MR imaging, there were no differences among progress in disability, disability improvement, and the stable groups in whole-brain volume (P = .71) or lateral ventricle volume (P = .74). During follow-up, patients with disability improvement had the lowest annualized percentage lateral ventricle volume change (1.6% ± 2.7%) followed by patients who were stable (2.1% ± 3.7%) and had progress in disability (4.1% ± 5.5%), respectively (P < .001). The annualized percentage brain volume change values were -0.7% ± 0.7% for disability improvement, -0.8% ± 0.7% for stable, and -1.1% ± 1.1% for progress in disability (P = .001). Patients with MS who improve in their clinical disability develop less brain atrophy across time compared with those who progress.

Aging and Brain Atrophy in Multiple Sclerosis.

Brain atrophy accelerates at the age of 60 in healthy individuals (HI) and at disease onset in multiple sclerosis (MS) patients. Whether there is an exacerbating effect of aging superimposed on MS-related brain atrophy is unknown. We estimated the aging effect on lateral ventricular volume (LVV) and whole brain volume (WBV) changes in MS patients. 1,982 MS patients (mean follow-up: 4.8 years) and 351 HI (mean follow-up: of 3.1 years), aged from 20 to 79 years old (yo), were collected retrospectively. Percent LVV change (PLVVC) and percent brain volume change (PBVC) on 1.5T and 3T MRI scanners (median of 3.9 scans per subject) were calculated. These were determined between all-time points and subjects were divided in six-decade age groups. MRI differences between age groups were calculated using analysis of covariance (ANCOVA). Compared to HI, at first MRI, MS patients had significantly increased LVV in the age groups: 30-39 yo, 40-49 yo, 50-59 yo, 60-69 yo (all P < .0001), and 70-79 yo (P = .029), and decreased WBV in the age groups: 20-29 yo (P = .024), 30-39 yo (P = .031), 40-49 yo, and 50-59 yo (all P < .0001). Annualized PLVVC was significantly different between the age groups 20-59 and 60-79 yo in MS patients (P = .005) and HI (P < .0001), as was for PBVC in MS patients (P = .001), but not for HI (P = .521). There was a significant aging interaction effect in the annualized PLVVC (P = .001) between HI and MS patients, which was not observed for the annualized PBVC (P = .380). Development of brain atrophy manifests progressively in MS patients, and occurs with a different pattern, as compared to aging HI. PLVVC increased across age in HI as compared to MS, while PBVC decreased across ages in both HI and MS.

Hypertension and heart disease are associated with development of brain atrophy in multiple sclerosis: a 5-year longitudinal study.

Cardiovascular diseases (CVDs) are more frequent in multiple sclerosis (MS) patients when compared to controls. In particular, CVDs are linked with higher accumulation of lesions and advanced brain atrophy. To investigate whether CVDs contribute to accelerated lesion accumulation and brain atrophy over 5 years in patients with MS. 194 MS patients and 43 controls without neurologic disease were followed for 5 years. Full physical, neurological evaluation, and structured questionnaire investigating CVD and risk factors (hypertension, hyperlipidemia, heart disease, smoking, diabetes, obesity/overweight) were collected using interview-based questionnaire and further cross-reference with electronic medical records. Lesion and brain atrophy outcomes were assessed with 3T MRI. ANCOVA adjusted for age, gender, and disease duration were used accordingly. False discovery rate correction was performed using Benjamini-Hochberg correction. Patients with diagnosis of heart disease showed higher white matter and whole brain volume loss compared to those without (-4.2% vs. -0.7%, P = 0.01 and -3.4% vs. -1.6%, P = 0.01, respectively). The percentage lateral ventricle volume change in MS patients with hypertension was higher compared to non-hypertensive patients (24.5% vs. 14.1%, P = 0.05). Hyperlipidemia, smoking, and obesity/overweight were not associated with progression of MRI-derived outcomes. CVDs did not contribute to larger lesion volume accrual over the 5-year period. The presence of CVDs was not associated with MRI-derived changes in the controls. Hypertension and heart disease contribute to advanced brain atrophy in MS patients. CVDs did not contribute to additional lesion accrual. CVD comorbidities in MS patients may contribute to neurodegenerative tissue injury that can be detected with brain MRI.

Hypertension and heart disease are independently associated with development of brain atrophy in multiple sclerosis patients. A 5-year longitudinal study (P2.345)

Hypertension and heart disease are independently associated with development of brain atrophy in multiple sclerosis patients. A 5-year longitudinal study (P2.345)

Dynamics of changes in the content of thyroid hormones and some neurotransmitters in brain of rats with experimental Alzheimer’s disease

Objective: Alzheimer's disease is one of the most common neurodegenerative diseases, and mechanisms of its development have been studied for many years. The aim of the research was to study the content of thyroid-stimulating hormone (TSH), thyroid hormones and tau protein in the blood serum, as well as the content of thyroid hormones and some neurotransmitters in the cerebral cortex in the dynamics of experimental Alzheimer’s disease in rats. Materials and methods. The experiment was performed on 45 WAG rats, which were divided into 3 groups. The first group was the control one. Animals from the second and third groups were intraperitoneally administered with scopolamine for 14 and 27 days, which led to the development of Alzheimer's disease. Brain homogenate was prepared. Concentrations of T3, T4 in blood serum and homogenates of the cerebral cortex, as well as TSH and tau protein in serum, were determined by ELISA. Determination of the content of neurotransmitter amino acids (aspartate and glutamate) was carried out by thin-layer chromatography. The content of dopamine and norepinephrine in the cerebral cortex homogenate was determined by column chromatography, and acetylcholine levels were measured by spectrophotometry. Morphological examination included staining of brain tissue with congo-rot + hematoxylin. Results. It was established that in cerebral cortex homogenates of rats with experimental Alzheimer’s disease the T3 content was reduced, and T4 levels were similar to rats of the control group, which in combination with the normal concentration of thyroid hormones in blood serum indicates the development of local hypothyroidism in the cerebral cortex. In rats with Alzheimer's disease, glutamic and aspartic acid levels were increased against the background of GABA reduction. There was also a decrease in the levels of noradrenaline and dopamine in the cerebral cortex homogenates, which contributes to the abnormal energy metabolism and impaired cognitive functions. Morphological study demonstrated the presence of congophilic masses in the brain tissue and in the walls of small arteries with the development of brain atrophy. Conclusions. Alzheimer's disease caused by the administration of scopalamine is characterized by the development of local hypothyroidism in the cerebral cortex, an increase in the level of glutamic and aspartic acids with a decrease in GABA, a decrease in the level of dopamine and norepinephrine in the cerebral cortex.

Brain atrophy in picornavirus‐infected FVB mice is dependent on the H‐2Dbclass I molecule

Brain atrophy is a common feature of numerous neurologic diseases in which the role of neuroinflammation remains ill-defined. In this study, we evaluated the contribution of major histocompatibility complex class I molecules to brain atrophy in Theiler's murine encephalomyelitis virus (TMEV)-infected transgenic FVB mice that express the Db class I molecule. FVB/Db and wild-type FVB mice were evaluated for changes in neuroinflammation, virus clearance, neuropathology, and development of brain atrophy via T2-weighted MRI and subsequent 3-dimensional volumetric analysis. Significant brain atrophy and hippocampal neuronal loss were observed in TMEV-infected FVB/Db mice, but not in wild-type FVB mice. Brain atrophy was observed at 1 mo postinfection and persisted through the 4-mo observation period. Of importance, virus-infected FVB/Db mice elicited a strong CD8 T-cell response toward the immunodominant Db-restricted TMEV-derived peptide, VP2121-130, and cleared TMEV from the CNS. In addition, immunofluorescence revealed CD8 T cells near virus-infected neurons; therefore, we hypothesize that class I restricted CD8 T-cell responses promote development of brain atrophy. This model provides an opportunity to analyze the contribution of immune cells to brain atrophy in a system where persistent virus infection and demyelination are not factors in long-term neuropathology.-Huseby Kelcher, A. M., Atanga, P. A., Gamez, J. D., Cumba Garcia, L. M., Teclaw, S. J., Pavelko, K. D., Macura, S. I., Johnson. A. J. Brain atrophy in picornavirus-infected FVB mice is dependent on the H-2Db class I molecule.

Cerebrospinal fluid levels of neurofilament and tau correlate with brain atrophy in natalizumab-treated multiple sclerosis.

Brain atrophy is related to clinical deterioration in multiple sclerosis (MS) but its association with intrathecal markers of inflammation or neurodegeneration is unclear. Our aim was to investigate whether cerebrospinal fluid (CSF) markers of inflammation or neurodegeneration are associated with brain volume change in natalizumab-treated MS and whether this change is reflected in non-lesional white matter metabolites. About 25 patients with natalizumab-treated MS were followed for 3 years with assessment of percentage brain volume change (PBVC) and absolute quantification of metabolites with proton magnetic resonance spectroscopy (1 H MRS). Analyses of inflammatory [interleukin 1β (IL-1β), IL-6, C-X-C motif chemokine 8 (CXCL8), CXCL10, CXCL11, C-C motif chemokine 22] and neurodegenerative [neurofilament light protein (NFL), glial fibrillary acidic protein, myelin basic protein, tau proteins] markers were done at baseline and 1-year follow-up. The mean decline in PBVC was 3% at the 3-year follow-up, although mean 1 H MRS metabolite levels in non-lesional white matter were unchanged. CSF levels of NFL and tau at baseline correlated negatively with PBVC over 3 years (r = -0.564, P = 0.012, and r = -0.592, P = 0.010, respectively). A significant 3-year whole-brain atrophy was not reflected in mean metabolite change of non-lesional white matter. In addition, our results suggest that CSF levels of NFL and tau correlate with brain atrophy development and may be used for evaluating treatment response in inflammatory active MS.

Homocysteine, Liver Function Derangement and Brain Atrophy in Alcoholics.

Hyperhomocysteinemia may be involved in the development of brain atrophy in alcoholics. Its pathogenesis is multifactorial. In the present study, we analyse the relationship between homocysteine levels and brain atrophy, and the relative weight of co-existing factors such as liver function impairment, the amount of ethanol consumed, serum vitamin B12, B6, and folic acid levels on homocysteine levels and brain alterations in alcoholic patients. We included 59 patients admitted to this hospital for major withdrawal symptoms and 24 controls. The mini-mental state examination test and a brain computed tomography (CT) scan were performed and several indices were calculated. Serum levels of homocysteine, folic acid, vitamin B6 and vitamin B12 were determined. Liver function was assessed by Child-Pugh score. The daily consumption of ethanol in grams per day and years of addiction were recorded. A total of 83.6% and 80% of the patients showed cerebellar or frontal atrophy, respectively. Patients showed altered values of brain indices, higher levels of homocysteine and vitamin B12, but lower levels of folic acid, compared with controls. Homocysteine, B12 and liver function variables showed significant correlations with brain CT indices. Multivariate analyses disclosed that Pugh's score, albumin and bilirubin were independently related to cerebellar atrophy, frontal atrophy, cella index or ventricular index. Serum vitamin B12 was the only factor independently related to Evans index. It was also related to cella index, but after bilirubin. Homocysteine levels were independently related to ventricular index, but after bilirubin. Vitamin B12 and homocysteine levels are higher among alcoholics. Liver function derangement, vitamin B12 and homocysteine are all independently related to brain atrophy, although not to cognitive alterations. Hyperhomocysteinemia has been described in alcoholics and may be related to brain atrophy, a reversible condition with an obscure pathogenesis. We studied 59 patients and found that liver function derangement, vitamin B12 and homocysteine levels are all independently related to brain atrophy assessed by computed tomography, although we found no association between these parameters and cognitive alterations.

Transgenic expression of H-2Db class I molecules influences the development of brain atrophy during Picornavirus infection

Abstract Brain atrophy is a common feature of numerous neurological diseases in which the role of neuroinflammation remains poorly defined. We have previously demonstrated the development of brain and spinal cord atrophy in the Theiler’s murine encephalomyelitis virus (TMEV) model of multiple sclerosis. However, cellular and molecular mechanisms of brain atrophy remain poorly understood. We therefore evaluated the contribution of major histocompatibility (MHC) class I molecules in atrophy development during TMEV infection. To accomplish this, we created a novel transgenic FVB/NJ mouse by introducing the H-2Db (Db) class I molecule. Expression of Db class I molecule confers resistance to persistent TMEV infection and demyelination in the normally susceptible FVB/NJ strain (H2-Dq class I haplotype). Next, we compared the development of brain atrophy, assessed by volumetric analysis of T2-weighted MRIs, in FVB/Db mice to wild-type FVB/NJ mice following viral infection. FVB/NJ mice did not significant brain develop atrophy over 4 months, whereas significant brain atrophy was observed in the FVB/Db mice. FVB/Db mice also developed a significant increase in the overall number of CNS infiltrating CD8 T cells and a strong CD8 T cell response towards an immunodominant Db TMEV epitope, VP2121-130. A number of CD8 T cells were also observed in close proximity to virus infected neurons. We therefore propose a hypothesis that class I restricted CD8 T cell responses promote the development of brain atrophy. This model provides a unique opportunity to analyze the contribution of immune cells to neuronal loss and brain atrophy in a system where persistent virus infection and demyelination are not confounding variables.