Total Atrophy Research Articles

Altered Brain Volume, Microstructure Metrics and Functional Connectivity Features in Multiple System Atrophy.

In order to deeply understand the specific patterns of volume, microstructure, and functional changes in Multiple System Atrophy patients with cerebellar ataxia syndrome (MSA-c), we perform the current study by simultaneously applying structural (T1-weighted imaging), Diffusion tensor imaging (DTI), functional (BOLD fMRI) and extended Network-Based Statistics (extended-NBS) analysis. Twenty-nine MSA-c type patients and twenty-seven healthy controls (HCs) were involved in this study. First, we analyzed the whole brain changes of volume, microstructure, and functional connectivity (FC) in MSA-c patients. Then, we explored the correlations between significant multimodal MRI features and the total Unified Multiple System Atrophy Rating Scale (UMSARS) scores. Finally, we searched for sensitive imaging biomarkers for the diagnosis of MSA-c using support vector machine (SVM) classifier. Results showed significant grey matter atrophy in cerebellum and white matter microstructural abnormalities in cerebellum, left fusiform gyrus, right precentral gyrus and lingual gyrus. Extended-NBS analysis found two significant different connected components, featuring altered functional connectivity related to left and right cerebellar sub-regions, respectively. Moreover, the reduced fiber bundle counts at right Cerebellum_3 (Cbe3) and decreased fractional anisotropy (FA) values at bilateral Cbe9 were negatively associated with total UMSARS scores. Finally, the significant features at left Cbe9, Cbe1, and Cbe7b were found to be useful as sensitive biomarkers to differentiate MSA-c from HCs according to the SVM analysis. These findings advanced our understanding of the neural pathophysiological mechanisms of MSA from the perspective of multimodal neuroimaging.

CLINICAL EVALUATION OF ATROPHIC CHANGES IN TISSUES OF PROSTHETIC IMPRESSION AREA IN TREATMENT OF PATIENTS WITH COMPLETE REMOVABLE PLATE PROSTHESIS WITH THE USE OF OZONE THERAPY

One of the main methods of treatment of patients with complete absence of teeth is the use of complete removable plate prosthesis (CRPP) made of acrylic plastics. Violation of the polymerization regime and increased amount of residual monomer in acrylic prostheses lead to a number of complications in the tissues of the prosthetic impression area. According to our previous experimental researches, the use of ozone therapy is a promising area for the prevention and treatment of inflammatory processes and microbial lesions of the oral mucosa. Therefore, the aim of our research was to evaluate the effect of monitoring the level of residual monomer in the bases of prostheses and the influence of ozone therapy on atrophic changes in the tissues of prosthetic impression area in the treatment of patients with CRPP.
 118 patients with CRPP were examined and underwent of orthopedic treatment. Patients were divided into the following groups:
 Group 1 consisted of 33 patients who underwent of orthopedic treatment with complete removable plate prostheses made of plastic "Ftorax" by conventional methods.
 Group 2 included 39 patients with complete removable plate prostheses made of plastic "Ftorax" with controlled level of residual monomer by the proposed method of spectrophotometry.
 Group 3 consisted of 46 patients with complete removable plate prostheses made of plastic "Ftorax" with controlled level of residual monomer by the proposed method of spectrophotometry using the course of ozone therapy.
 Each group was further divided into subgroups; the patients underwent of orthopedic treatment on the upper "a" and lower "b" jaw.
 The intensity of atrophic changes in alveolar processes of the jaws was assessed in the dynamics of orthopedic treatment in certain regions (A, B, C, D, E) of the prosthetic impression area and determining of the total atrophy of the alveolar process of the jaws after 1 week, 1, 3, 6, 12 months of a removable prosthesis using. Ozone generation was performed using the Ozone DTA (APOZA Enterprise Co., Ltd., Taiwan), which is recommended for clinical use in dental practice.
 There is a direct dependence of CRPP fixation on the intensity of atrophic changes in alveolar processes of the upper and lower jaws, which were less pronounced in patients with residual monomer control in prosthetic bases and in combination with ozone therapy of mucosa in the prosthetic impression area. Atrophic changes in mandibular alveolar processes have a more significant effect on the fixation of complete removable plate prostheses in comparison with atrophic changes of the upper jaw. A probable regularity was revealed during the period of 1-12 months of orthopedic treatment of patients with CRPP, which indicates more uniform atrophies in different areas A, B, C, D, E on the upper jaw but the atrophic changes are not uniform on the lower jaw. A course of ozone therapy of mucosa in the prosthetic impression area during orthopedic treatment of patients with CRPP in combination with control of the level of residual monomer in the bases of removable prostheses significantly slows down the process of atrophic changes.
 The obtained clinical results substantiate the possibility and expediency of using CRPP from acrylic plastic made with control of the level of residual monomer by the proposed method of spectrophotometry and the use of ozone therapy to prevent atrophic changes of alveolar processes of the jaws and prosthetic stomatitis.

Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years

Background: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study. Objective: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years. Methods: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group). Results: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66–0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65–0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term. Conclusion: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation. Trial registration number: NCT01665144

Первинний імунодефіцит: IPEX-синдром. Огляд літератури та клінічний випадок

IPEX-syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is a severe inherited X-linked disease from the group of primary immunodeficiencies associated with mutations in the FOXP3 gene, which encodes a key transcription factor for T-regulatory lymphocytes. In the pathogenesis of the disease the main role plays disorder of maturation of CD25 + CD4 + -T-regulatory lymphocytes (TR), which carry out negative selection of autoreactive clones of T- and B-lymphocytes, resulting in loss of autotolerance and early development of multiorgan autoimmune pathology in combination with severe violation of antiviral and antibacterial immunity. The typical clinical picture of IPEX-syndrome is a triad: autoimmune enteropathy, endocrinopathy (diabetes mellitus type 1, autoimmune thyroiditis), skin and/or mucosal lesions, but any combination of autoimmune pathology or isolated organ damage is possible. At the same time, intestinal lesions (autoimmune enteropathy) are found in almost 100% of patients. Laboratory immunological markers of IPEX-syndrome are absent (the disease can be detected only by genetic testing - panel sequencing of genes), which, along with the variability of clinical manifestations, creates significant diagnostic difficulties. The article presents a clinical case of IPEX-syndrome, the clinical features of which were isolated enteropathy without clinical and laboratory signs of autoimmune damage to other organs, as well as severe lesions of the small intestinal mucosa (total villi atrophy) and rapid disease progression despite late onset (during second year of life). Although immunologists associate the late onset with «soft» mutations in the gene, easier course and more favorable prognosis. Laboratory features of this case were: negative serological markers of autoimmune intestinal lesions and elevated levels of T-regulatory lymphocytes CD4 + CD25 + CD127low +, although IPEX-syndrome is characterized by a decrease or absence of T-regulatory cells. IPEX-syndrome in this patient was confirmed by genetic research - sequencing of the FOXP3 gene revealed a pathogenic mutation с. 736-2А>Т (Splice acceptor). The research was carried out in accordance with the principles of the Helsinki declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors. Key words: infants, primary immunodeficiency, IPEX-syndrome, FOXP3 gene mutations, autoimmune enteropathy, diagnosis.

Mediterranean-Type Diet and Brain Structural Change from 73 to 79 Years in the Lothian Birth Cohort 1936

ObjectivesTo test whether Mediterranean-type Diet (MeDi) at age 70 years is associated with longitudinal trajectories of total brain MRI volume over a six-year period from age 73 to 79.DesignCohort study which uses a correlational design.SettingParticipants residing in the Lothian region of Scotland and living independently in the community.ParticipantsA relatively healthy Scottish sample drawn from the Lothian Birth Cohort 1936.MeasurementsTotal brain volume measurements were available at ages 73, 76 and 79 (N ranged 332 to 563). Adherence to the MeDi was based on food frequency questionnaire data collected three years before the baseline imaging scans, and was used in growth curve models to predict the trajectory of total brain volume change.ResultsNo association was found (p>.05) between adherence to the MeDi at age 70 and total brain volume change from 73 to 79 years in minimally-adjusted (sex) or fully adjusted models controlling for additional health confounders.ConclusionsVariation in adherence to the MeDi was not predictive of total brain atrophy over a six-year period. This suggests that previous findings of dietary associations with brain volume are not long lasting or become less important as ageing-related conditions account for greater variation in brain volume change. More frequent collection of dietary intake data is needed to clarify these findings.

Association of APOE ε4 with cerebral gray matter volumes in non-demented older adults: The MEMENTO cohort study

Data on 2,045 non-demented individuals with memory complaints were drawn from the Memento cohort study to examine the association between Apolipoprotein E ε4 allele (APOE4) and regional brain gray matter volumes. Linear regression was used to examine the association of APOE4 and measures of regional gray matter volumes in cross-sectional analysis and change therein using longitudinal analyses based on two brain MRI performed at baseline and at two-year follow-up. Overall, in analyses adjusted for age, sex, and intracranial volume, the presence of APOE4 was associated with lower total gray matter volume at baseline and with a higher atrophy rate over the follow-up. The hippocampus and entorhinal cortex were the two gray matter regions most associated with APOE4. Further adjustment for cardiovascular risk factors had little impact on these associations. There was an interaction between age, APOE4 status and total brain volume atrophy rate, with evidence of an earlier age at onset of atrophy in hippocampal volume in APOE4 carriers compared to non-carriers. Those results are in accordance with the role of medial temporal structures in the greater risk of dementia observed in people carrying the APOE4 allele.

Functional connectivity dynamics reflect disability and multi-domain clinical impairment in patients with relapsing-remitting multiple sclerosis

Background & AimMultiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with deficits in cognitive and motor functioning. While structural brain changes such as demyelination are an early hallmark of the disease, a characteristic profile of functional brain alterations in early MS is lacking. Functional neuroimaging studies at various disease stages have revealed complex and heterogeneous patterns of aberrant functional connectivity (FC) in MS, with previous studies largely being limited to a static account of FC. Thus, it remains unclear how time-resolved FC relates to variance in clinical disability status in early MS. We here aimed to characterize brain network organization in early MS patients with time-resolved FC analysis and to explore the relationship between disability status, multi-domain clinical outcomes and altered network dynamics. MethodsResting-state functional MRI (rs-fMRI) data were acquired from 101 MS patients and 101 age- and sex-matched healthy controls (HC). Based on the Expanded Disability Status Score (EDSS), patients were split into two sub-groups: patients without clinical disability (EDSS ≤ 1, n = 36) and patients with mild to moderate levels of disability (EDSS ≥ 2, n = 39). Five dynamic FC states were extracted from whole-brain rs-fMRI data. Group differences in static and dynamic FC strength, across-state overall connectivity, dwell time, transition frequency, modularity, and global connectivity were assessed. Patients’ impairment was quantified as custom clinical outcome z-scores (higher: worse) for the domains depressive symptoms, fatigue, motor, vision, cognition, total brain atrophy, and lesion load. Correlation analyses between functional measures and clinical outcomes were performed with Spearman partial correlation analyses controlling for age. ResultsPatients with mild to moderate levels of disability exhibited a more widespread spatiotemporal pattern of altered FC and spent more time in a high-connectivity, low-occurrence state compared to patients without disability and HCs. Worse symptoms in all clinical outcome domains were positively associated with EDSS scores. Furthermore, depressive symptom severity was positively related to functional dynamics as measured by state-specific global connectivity and default mode network connectivity with attention networks, while fatigue and motor impairment were related to reduced frontoparietal network connectivity with the basal ganglia. ConclusionsDespite comparably low impairment levels in early MS, we identified distinct connectivity alterations between patients with mild to moderate disability and those without disability, and these changes were sensitive to clinical outcomes in multiple domains. Furthermore, time-resolved analysis uncovered alterations in network dynamics and clinical correlations that remained undetected with conventional static analyses, showing that accounting for temporal dynamics helps disentangle the relationship between functional alterations, disability status, and symptoms in early MS.

Diffusion imaging of fornix and interconnected limbic deep grey matter is linked to cognitive impairment in multiple sclerosis.

Diffusion tensor imaging (DTI) and volumetric magnetic resonance imaging (MRI) have shown white matter (WM) and deep grey matter (GM) abnormalities in the limbic system of multiple sclerosis (MS) participants. Structures like the fornix have been associated with cognitive impairment (CI) in MS, but the diffusion metrics are often biased by partial volume effects from cerebrospinal fluid (CSF) due to its small bundle size and intraventricular location. These errors in DTI parameter estimation worsen with atrophy in MS. The goal here was to evaluate DTI parameters and volumes of the fornix, as well as associated deep GM structures like the thalamus and hippocampus, with high-resolution fluid-attenuated inversion recovery (FLAIR)-DTI at 3T in 43 MS patients, with and without CI, versus 43 controls. The fornix, thalamus and hippocampus displayed atrophy and/or abnormal diffusion metrics, with the fornix showing the most extensive changes within the structures studied here, mainly in CI MS. The affected fornix volumes and diffusion metrics were associated with thalamic atrophy and atypical diffusion metrics in interconnected limbic GM, larger total lesion volume and global brain atrophy. Lower fractional anisotropy (FA) and higher mean and radial diffusivity in the fornix, lower hippocampus FA and lower thalamus volume were strongly correlated with CI in MS. Hippocampus FA and thalamus atrophy were negatively correlated with fatigue and longer time since MS symptoms onset, respectively. FLAIR-DTI and volumetric analyses provided methodologically superior evidence for microstructural abnormalities and extensive atrophy of the fornix and interconnected deep GM in MS that were associated with cognitive deficits.

The association between isolated hypertension and brain volumes in UK Biobank

AbstractBackgroundHypertension is a well‐established risk factor for cognitive impairment, brain atrophy and dementia. Isolated hypertension is where either systolic or diastolic blood pressure is high and the other measure is normal. It is unknown the impact of isolated hypertension on brain atrophy and how it compares to non isolated hypertension (NIH). Therefore it is important to investigate the impact of isolated hypertension to help understand its impact on future dementia risk and cognitive decline. We investigated relationships between isolated hypertension on brain volumes using the largest cohort of healthy individuals from the United Kingdom.MethodUsing the UK Biobank cohort, we carried out a cross‐sectional study using 31,513 participants [mean age 63 years, 53% female] with BP measurements and brain MRI data. We used linear regression models to determine the associations between isolated systolic (ISH) and isolated diastolic hypertension (IDH) split by BP medication use with brain volumes (total volume, total grey matter, hippocampal and white matter hyperintensities (WMH)).ResultIndividuals with ISH and taking BP medications (n = 3137) had smaller grey matter volumes (β = ‐0.04 [95%CI ‐0.07 to ‐0.03]), and greater WMH (β = 0.25 [95%CI 0.21 to 0.28]) compared to normotensive individuals (n = 14677). Interestingly, individuals with IDH and taking BP medications (n =140) also had smaller total grey matter (β = ‐0.11 [95%CI ‐0.19 to ‐0.04]) and larger WMH (β = 0.26 [95%CI 0.12 to 0.41]). Individuals with ISH have comparable total grey matter atrophy to individuals with NIH not taking medications (ISH β = ‐0.044 vs NIH β = ‐0.027) and have comparable WMHs (ISH β = 0.25 vs NIH β = 0.022).ConclusionOur results indicate that individuals with isolated hypertension have greater total grey matter atrophy and vascular pathology and this atrophy is similar to certain subsets of individuals with non isolated hypertension. These results provide a further emphasis of preventative strategies particularly focusing on isolated systolic hypertension as well as non isolated hypertension in maintaining brain health to reduce dementia risk earlier in life.

CSF and blood plasma mass spectrometry measures of Aβ, tau, and NfL species and longitudinal relationship to preclinical and clinical staging of amyloid and tau aggregation and clinical stage of Alzheimer’s disease

AbstractBackgroundRecent advances in the development of novel Alzheimer’s disease (AD) measures of amyloid, tau, and neurodegeneration in cerebrospinal fluid (CSF) and blood have enabled a better understanding of the links between amyloid‐beta (Aβ), tau species and neurodegeneration in the brain, CSF, and blood. The discoveries of novel tau species in CSF and blood, including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, have greatly expanded our understanding of tau biology and tau target development. The longitudinal Aβ, tau, and neurofilament light chain (NfL) changes previously measured in CSF are now being measured accurately in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.MethodWe analyzed longitudinal CSF and/or blood plasma mass spectrometry measures of Aβ42/Aβ40, multiple p‐tau species (including p‐tau217, 231, 181, 205, etc.), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in sporadic AD and dominantly inherited AD cohorts. Mass spectrometry results were compared to amyloid and tau aggregation measures by Positron Emission Tomography (PET) scans and clinical and cognitive measures in local and international clinical cohorts including ADNI, AIBL, BioFINDER, Mayo Clinic, the Knight ADRC, and the DIAN.ResultThe longitudinal results indicate that a pathophysiological cascade of events begin with altered CSF and blood plasma Aβ42/Aβ40 ratio, followed by increases in amyloid plaques as measured by amyloid PET, associated with increased phosphorylation of specific CSF tau species (e.g., p‐tau217, p‐tau181, etc.), before increases in p‐tau205, NfL, total tau concentrations, hypometabolism, and atrophy. Finally, some species of MTBR‐tau increase before or with tau aggregation by tau PET and onset of clinical symptoms and correlate with longitudinal tau aggregation and clinical progression.ConclusionThese findings indicate that CSF and blood plasma Aβ, p‐tau, MTBR‐tau and NfL measures are highly precise biomarkers of brain amyloidosis, tauopathy, and neurodegeneration and can accurately identify stages of preclinical and clinical AD.

Vascular Risk Factors and Cognition in Multiple System Atrophy.

Objective: Vascular risk factors have been reported to be associated with cognitive impairment (CI) in the general population, but their role on CI in multiple system atrophy (MSA) is unclear. This study aimed to explore the relationship between vascular risk factors and CI in patients with MSA.Methods: The clinical data and vascular risk factors were collected. The Montreal Cognitive Assessment tool was used to test the cognitive function of patients with MSA. Binary logistic regression was used to analyze the correlation between vascular risk factors and CI.Results: A total of 658 patients with MSA with a mean disease duration of 2.55 ± 1.47 years were enrolled. In MSA patients, hypertension was recorded in 20.2%, diabetes mellitus in 10.3%, hyperlipidemia in 10.2%, smoking in 41.2%, drinking in 34.8%, and obesity in 9.6%. The prevalence of CI in patients with MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C) was 45.0, 45.1, and 44.9%, respectively. In the binary logistic regression model, patients with more than one vascular risk factors were significantly more likely to have CI in MSA (OR = 4.298, 95% CI 1.456–12.691, P = 0.008) and MSA-P (OR = 6.952, 95% CI 1.390–34.774, P = 0.018), after adjusting for age, sex, educational years, disease duration, and total Unified multiple system atrophy rating scale scores.Conclusion: Multiple vascular risk factors had a cumulative impact on CI in MSA. Therefore, the comprehensive management of vascular risk factors in MSA should not be neglected.

Diffusion Tensor Imaging of the Olfactory System in Older Adults With and Without Hyposmia.

Objectives: To compare gray matter microstructural characteristics of higher-order olfactory regions among older adults with and without hyposmia.Methods: Data from the Brief Smell Identification Test (BSIT) were obtained in 1998–99 for 265 dementia-free adults from the Health, Aging, and Body Composition study (age at BSIT: 74.9 ± 2.7; 62% White; 43% male) who received 3T diffusion tensor imaging in 2006–08 [Interval of time: mean (SD): 8.01 years (0.50)], Apolipoprotein (ApoEε4) genotypes, and repeated 3MS assessments until 2011–12. Cognitive status (mild cognitive impairment, dementia, normal cognition) was adjudicated in 2011–12. Hyposmia was defined as BSIT ≤ 8. Microstructural integrity was quantified by mean diffusivity (MD) in regions of the primary olfactory cortex amygdala, orbitofrontal cortex (including olfactory cortex, gyrus rectus, the orbital parts of the superior, middle, and inferior frontal gyri, medial orbital part of the superior frontal gyrus), and hippocampus. Multivariable regression models were adjusted for total brain atrophy, demographics, cognitive status, and ApoEε4 genotype.Results: Hyposmia in 1998–99 (n = 57, 21.59%) was significantly associated with greater MD in 2006–08, specifically in the orbital part of the middle frontal gyrus, and amygdala, on the right [adjusted beta (p value): 0.414 (0.01); 0.527 (0.01); respectively].Conclusion: Older adults with higher mean diffusivity in regions important for olfaction are more likely to have hyposmia up to ten years prior. Future studies should address whether hyposmia can serve as an early biomarker of brain microstructural abnormalities for older adults with a range of cognitive functions, including those with normal cognition.

Correlation between Topographic Progression of Geographic Atrophy and Visual Acuity Changes.

PurposeTo analyze topographic progression of geographic atrophy with different concentric circles centered on the fovea in correlation with decrease of visual acuity.MethodsWe retrospectively analyzed 36 eyes of 26 patients diagnosed with geographic atrophy and followed at least 1 year. One millimeter circular area at the foveal center were defined as zone 1, and doughnut shape areas from between 1 and 2 mm to between 5 and 6 mm were defined as zone 2 to 6. Then, changes of geographic atrophy area in each zone were measured with semi-automatic software. Correlation analysis and regression analysis were performed to determine the relationship between changes in visual acuity and atrophic area in each zone.ResultsMean age was 76.9 years and follow-up period were 3.38 years. The mean atrophic area increased from 8.09 to 16.34 mm2 and visual acuity decreased from 0.39 to 0.69 on logarithm of the minimal angle of resolution. Mean change of total geographic atrophy area was not significantly correlated with visual acuity decrease. While geographic atrophy progression within zone 1, 2, and 3 showed significant causal relationship with decrease of visual acuity (all, p < 0.05).ConclusionsIn contrast to the total geographic atrophy area, progression of geographic atrophy in parafoveal area was significantly correlated with decrease of visual acuity.

Assessment of structural brain changes in patients with type 2 diabetes mellitus using the MRI-based brain atrophy and lesion index.

Patients with type 2 diabetes mellitus (T2DM) often have cognitive impairment and structural brain abnormalities. The magnetic resonance imaging (MRI)-based brain atrophy and lesion index can be used to evaluate common brain changes and their correlation with cognitive function, and can therefore also be used to reflect whole-brain structural changes related to T2DM. A total of 136 participants (64 men and 72 women, aged 55-86 years) were recruited for our study between January 2014 and December 2016. All participants underwent MRI and Mini-Mental State Examination assessment (including 42 healthy control, 38 T2DM without cognitive impairment, 26 with cognitive impairment but without T2DM, and 30 T2DM with cognitive impairment participants). The total and sub-category brain atrophy and lesion index scores in patients with T2DM with cognitive impairment were higher than those in healthy controls. Differences in the brain atrophy and lesion index of gray matter lesions and subcortical dilated perivascular spaces were found between non-T2DM patients with cognitive impairment and patients with T2DM and cognitive impairment. After adjusting for age, the brain atrophy and lesion index retained its capacity to identify patients with T2DM with cognitive impairment. These findings suggest that the brain atrophy and lesion index, based on T1-weighted and T2-weighted imaging, is of clinical value for identifying patients with T2DM and cognitive impairment. Gray matter lesions and subcortical dilated perivascular spaces may be potential diagnostic markers of T2DM that is complicated by cognitive impairment. This study was approved by the Medical Ethics Committee of University of South China (approval No. USC20131109003) on November 9, 2013, and was retrospectively registered with the Chinese Clinical Trial Registry (registration No. ChiCTR1900024150) on June 27, 2019.

Progression of optic atrophy in traumatic optic neuropathy: retrograde neuronal degeneration in humans.

We used optical coherence tomography (OCT) to document the time course of retrograde neuronal degeneration following indirect optic nerve injury. We retrospectively studied patients diagnosed with unilateral indirect traumatic optic neuropathy (TON). Patients with total or near-total optic atrophy were included. All patients underwent complete ophthalmological examinations, including OCT imaging, within 1day and at 1, 2, 3, 4, 6, 8, 12, 24, and 48weeks after trauma. The mean thicknesses of the circumpapillary retinal nerve fiber layer (cpRNFL) and macular retinal ganglion cell-inner plexiform layer (mGCIPL) decreased significantly at 2weeks after trauma (p = 0.027 and p = 0.043). Changes in mGCIPL thickness preceded changes in cpRNFL thickness. The rates of reduction in mGCIPL and cpRNFL thicknesses were greatest between 2 to 4weeks and 4 to 6weeks after trauma. The reduction in mGCIPL thickness then slowed, and stabilized at 12weeks after trauma. The proportions of cpRNFL and mGCIPL losses at 2, 4, 6, 8, and 12weeks compared to 24weeks were 17.1, 33.7, 59.8, 77.9, and 87.9% and 30.0, 73.3, 76.1, 88.3, and 97.9%, respectively. OCT revealed optic atrophy progression 2weeks after trauma, which was most rapid from 2 to 6weeks, and then gradually stabilized. Loss of retinal ganglion cell bodies and dendrites seemed to precede the axonal degeneration. Observations of morphological changes in retinal layers using OCT in TON patients improve our understanding of retrograde neuronal degeneration of the central nervous system.

Clinical Spectrum of Ocular and Visual Dysfunction in Children with Periventricular Leukomalacia: A Need for an Interdisciplinary Approach

AbstractThe study aimed to evaluate the ocular motility and visual and optic disc abnormalities in children diagnosed with periventricular leukomalacia (PVL). A retrospective analysis was performed on 51 consecutive children who had ophthalmic symptoms and were diagnosed with PVL by using magnetic resonance imaging. The patients were assessed for visual function, strabismus, cycloplegic refraction, fundus examination, and if appropriate, spectral-domain optical coherence tomography and visual field testing were applied. The primary outcome measures were the prevalence and visual and ocular motility dysfunctions. Mean age was 5.72 ± 2.6 years (range = 1–12), median birth weight was 2,740 g (range = 1,240–3,460), and median gestational age was 34 weeks (range = 28–38). In total, 21 patients (39.6%) had neurological deficit, 11 (21.5%) had intellectual disability, and 19 (37.2%) had no neurological symptom. In the spherical equivalent refractive error and cylinder power analysis, 10 patients had ≥3.0 D myopia, 15 had ≥3.0 D hyperopia, and eight had ≥2.50 D astigmatism. Thirteen (25.4%) children had a best-corrected visual acuity between 20/40 and 20/20 for Snellen card, while 9 (17.6%) had strabismic amblyopia and 6 (11.7%) had anisometropic amblyopia. Manifest strabismus was present in 35 patients (68.6%); of whom 12 had esotropia (23.5%), 16 had exotropia (31.3%) and 6 had vertical deviation (11.7%). Manifest or latent nystagmus was detected in 14 patients (27.4%). In 28 patients (54.9%), there was optic nerve abnormality. Two patients had hypoplastic disc, 14 had optic disc pallor, 7 had large cupping, and 5 had total optic atrophy. Six subjects underwent reliable visual field (VF) examinations, and all six had abnormal VFs, with inferior fields being most affected. Ocular motility disorders, optic nerve abnormalities, VF defects, and low visual acuity are common findings in this cohort of PVL patients and maybe the only presenting signs of the disease. The recognition of the visual disabilities and implementation of early rehabilitation may have a significant benefit in these children.

Model Structure Uncertainty in the Characterization and Growth of Geographic Atrophy.

PurposeTo identify the most suitable model for assessing the rate of growth of total geographic atrophy (GA) by analysis of model structure uncertainty.MethodsModel structure uncertainty refers to unexplained variability arising from the choice of mathematical model and represents an example of epistemic uncertainty. In this study, we quantified this uncertainty to help identify a model most representative of GA progression. Fundus autofluorescence (FAF) images and GA progression data (i.e., total GA area estimation at each presentation) were acquired using Spectralis HRA+OCT instrumentation and RegionFinder software. Six regression models were evaluated. Models were compared using various statistical tests, [i.e., coefficient of determination (r2), uncertainty metric (U), and test of significance for the correlation coefficient, r], as well as adherence to expected physical and clinical assumptions of GA growth.ResultsAnalysis was carried out for 81 GA-affected eyes, 531 FAF images (range: 3–17 images per eye), over median of 57 months (IQR: 42, 74), with a mean baseline lesion size of 2.62 ± 4.49 mm2 (range: 0.11–20.69 mm2). The linear model proved to be the most representative of total GA growth, with lowest average uncertainty (original scale: U = 0.025, square root scale: U = 0.014), high average r2 (original scale: 0.92, square root scale: 0.93), and applicability of the model was supported by a high correlation coefficient, r, with statistical significance (P = 0.01).ConclusionsStatistical analysis of uncertainty suggests that the linear model provides an effective and practical representation of the rate and progression of total GA growth based on data from patient presentations in clinical settings.Translational RelevanceIdentification of correct model structure to characterize rate of growth of total GA in the retina using FAF images provides an objective metric for comparing interventions and charting GA progression in clinical presentations.

Adherence to dietary treatment and clinical factors associated with anti-transglutaminase antibodies in celiac disease during the follow-up

IntroductionIn clinical practice, celiac disease (CD) is monitored through anti-transglutaminase (TGA-IgA) antibody levels. The normalization of serum levels in successive periodic measurements indicates good response and adherence to dietary treatment. ObjectivesTo evaluate the factors associated with the evolution of TGA-IgA antibodies and their association with dietary non-compliance and diseases related to CD. MethodsThis prospective observational study was carried out in 254 participants, who were recruited from patients from a hospital in southern Spain. Information about sex, age, serological test results, HLA DQ2/DQ8 haplotypes, mucosal atrophy, gastrointestinal and extra-intestinal symptoms, as well as diagnosis of diseases related to CD, was collected. ResultsClinical manifestations, such as diarrhoea, abdominal pain and weight loss, showed differences according to sex and age. Children under 18 years of age presented a degree of total or severe atrophy of the intestinal villi. TGA-IgA antibodies concentrations were directly associated with the number of digestive disorders manifested by the patient and the record of dietary non-compliance and inversely related to the number of extra-digestive disorders. ConclusionsAdolescents between 12 and 18 years old were the least monitored as well as the group with more extra-intestinal symptoms reported. Therefore, it is necessary to develop strategies in clinical practice aimed at this population group and continuous monitoring should be implemented to improve life quality and reduce complications that may arise in the long term.

In Vivo/Ex Vivo EPR Investigation of the Brain Redox Status and Blood-Brain Barrier Integrity in the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by cognitive decline and total brain atrophy. Despite the substantial scientific effort, the pathological mechanisms underlying neurodegeneration in AD are currently unknown. In most studies, amyloid β peptide has been considered the key pathological change in AD. However, numerous Aβ-targeting treatments have failed in clinical trials. This implies the need to shift the research focus from Aβ to other pathological features of the disease. The aim of this study was to examine the interplay between mitochondrial dysfunction, oxidative stress and blood-brain barrier (BBB) disruption in AD pathology, using a novel approach that involves the application of electron paramagnetic resonance (EPR) spectroscopy. In vivo and ex vivo EPR spectroscopy using two spin probes (aminoxyl radicals) exhibiting different cell-membrane and BBB permeability were employed to assess BBB integrity and brain tissue redox status in the 5xFAD mouse model of AD. In vivo spin probe reduction decay was analyzed using a two-compartment pharmacokinetic model. Furthermore, 15 K EPR spectroscopy was employed to investigate the brain metal content. This study has revealed an altered brain redox state, BBB breakdown, as well as ROS-mediated damage to mitochondrial iron-sulfur clusters, and up-regulation of MnSOD in the 5xFAD model. The EPR spin probes were shown to be excellent in vivo reporters of the 5xFAD neuronal tissue redox state, as well as the BBB integrity, indicating the importance of in vivo EPR spectroscopy application in preclinical studies of neurodegenerative diseases.

Parasitism with Acanthocephalus Ranae in Frogs (Pelophylax Ridibundus Pallas 1771), from North-east Romania.

SummaryThe present study was carried out on 10 frogs, Pelophylax ridibundus (Pallas, 1771), captured near the river Bahlui, Iasi, between April and May, 2019, for the study of digestive helminths and their effect on the digestive tract. Macroscopic examination of the general cavity revealed distension of the small intestine. The sectioning of the intestinal wall revealed a variable number of parasites (1 – 12) with a whitish cylindrical body, anchored in the duodenal mucosa. The morphological study of the parasites confirmed the species as Acantocephalus ranae. The prevalence of the infection was 60 % and the average intensity was 4.83 ± 4.15. Lesions of the small intestine were characterized by catarrhal enteritis, hemorrhagic spots and ulcers on the mucosa, occlusion and obstruction of the intestinal lumen. Histologically, eosinophilic inflammatory infiltrate in the glandular crypts, mucosal and submucosal edema, fibrosis and conjunctival hyperplasia, total mucosal atrophy, were found. The infection with Acanthocephalus ranae in Pelophylax ridibundus caused severe pathological changes, conditioned by the intensity of the infection, aspects revealed for the first time in Romania.