Focal Atrophy Research Articles

Sleep disturbance associated with temporal lobe degeneration in frontotemporal dementia

AbstractBackgroundSleep abnormalities are increasingly recognized as markers and potential drivers of neurodegenerative proteinopathies. However, the sleep phenotype of less common dementias remains poorly characterised. In particular, clinical experience suggests that patients with focal temporal lobe degeneration in the frontotemporal dementia spectrum can experience sometimes striking sleep disruption. We recently had the opportunity to corroborate this clinical impression in a small series of representative patients participating in a larger cohort study.MethodsTo date, we have studied seven patients and three healthy age‐matched controls. The patients’ diagnoses comprise behavioural variant frontotemporal dementia associated with focal right temporal lobe atrophy (n = 3), semantic dementia associated with focal left temporal lobe atrophy (n = 2), young onset Alzheimer’s disease and logopenic aphasia (each n = 1). No participant had a past history of a clinical sleep disorder. Detailed data on sleep patterns, adapted standard sleep questionnaires (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale), overnight oximetry and neuropsychological test scores (covering domains of executive function, emotion processing, memory, and auditory perceptual learning) pre‐/post‐overnight sleep were collected with the assistance of patients’ caregivers.ResultsTwo patients with right temporal lobe atrophy and one with left temporal lobe atrophy had marked sleep fragmentation, in one right temporal case accompanied by frequent sleep attacks, with increased overall time in bed and/or attempting to sleep. Epworth and Pittsburgh indices in these patients indicated significant daytime sleepiness and reduced sleep quality; none had evidence of significant sleep apnoea on overnight oximetry. Comparatively mild clinical sleep disturbances were reported in patients with other dementia diagnoses. However, there was evidence for reduced auditory perceptual learning benefit from overnight sleep relative to healthy older controls, particularly in the patients with underlying Alzheimer pathology.ConclusionsThese preliminary findings suggest that focal temporal lobe degeneration may be associated with clinically relevant sleep disruption, as part of the more pervasive derangement of homeostasis in these syndromes. Further work is indicated to define the hypnic phenotype in detail, with sleep electrophysiology and correlative behavioural, neuroimaging and laboratory data in larger patient cohorts.

Novel genomic loci shape two neuroanatomical dimensions of AD in non‐demented populations

AbstractBackgroundArtificial intelligence has been in burgeoning demand to be applied to magnetic imaging resonance (MRI) data to parse the neuroanatomical heterogeneity of Alzheimer’s disease (AD) and/or mild cognitive impairment (MCI) (Wen et al., 2021a, 2021b; Yang et al., 2021). However, the genetic heterogeneity leading to this neuroanatomical heterogeneity, especially at the early asymptomatic stages, is not fully elucidated.MethodA deep semi‐supervised representation learning method, called Surreal‐GAN (Yang et al., 2022), was applied to T1‐weighted MRI from AD/MCI patients from ADNI to define the two neuroanatomical dimensions of AD at the symptomatic stages. The R1 dimension was characterized by widespread brain atrophy without an exclusive focus on the medial temporal lobe, whereas the R2 dimension showed focal medial temporal lobe atrophy (Wen et al., 2022). We then applied the trained model to 33,540 non‐demented individuals from UK Biobank. Imputed genotyping data were analyzed in genome‐wide association studies (GWAS). We performed multiple linear regressions controlling for confounding factors (e.g., age) via Plink (Purcell et al., 2007). We defined a genomic locus (represented by the top lead SNP) considering linkage disequilibrium. Finally, we manually queried all leading SNPs on GWAS Catalog (Buniello et al., 2019) to determine if the genomic loci were novel, provided they were not previously associated with any clinical traits.ResultGWAS discovered 24 genomic loci, of which 7 were novel for R1 and R2, respectively (Fig. 1). For R1, 8 mapped genes, based on physical positions, eQTL, and chromatin interactions, were associated with AD‐related traits in the literature. For example, the KDM2B gene from the genomic locus (rs9795600, P‐value = 1.13e‐08) was previously associated with AD (Gouveia et al., 2022). For R2, 13 mapped genes were associated with AD‐related traits. For example, the TESC gene from the genomic locus (rs77956314, P‐value = 9.99e‐29) was associated with neurofibrillary tangles measurement, which is formed by hyperphosphorylation of a microtubule‐associated protein known as tau in AD (Wang et al., 2020).ConclusionOur results confirmed genetic variants previously associated with AD and identified novel genomic loci contributing to this neuroanatomical heterogeneity. Further research is needed to understand these novel loci’s biological pathways and functional consequences.

Novel genomic loci shape two neuroanatomical dimensions of AD in non‐demented populations

AbstractBackgroundArtificial intelligence has been in burgeoning demand to be applied to magnetic imaging resonance (MRI) data to parse the neuroanatomical heterogeneity of Alzheimer’s disease (AD) and/or mild cognitive impairment (MCI) (Wen et al., 2021a, 2021b; Yang et al., 2021). However, the genetic heterogeneity leading to this neuroanatomical heterogeneity, especially at the early asymptomatic stages, is not fully elucidated.MethodA deep semi‐supervised representation learning method, called Surreal‐GAN (Yang et al., 2022), was applied to T1‐weighted MRI from AD/MCI patients from ADNI to define the two neuroanatomical dimensions of AD at the symptomatic stages. The R1 dimension was characterized by widespread brain atrophy without an exclusive focus on the medial temporal lobe, whereas the R2 dimension showed focal medial temporal lobe atrophy (Wen et al., 2022). We then applied the trained model to 33,540 non‐demented individuals from UK Biobank. Imputed genotyping data were analyzed in genome‐wide association studies (GWAS). We performed multiple linear regressions controlling for confounding factors (e.g., age) via Plink (Purcell et al., 2007). We defined a genomic locus (represented by the top lead SNP) considering linkage disequilibrium. Finally, we manually queried all leading SNPs on GWAS Catalog (Buniello et al., 2019) to determine if the genomic loci were novel, provided they were not previously associated with any clinical traits.ResultGWAS discovered 24 genomic loci, of which 7 were novel for R1 and R2, respectively (Fig. 1). For R1, 8 mapped genes, based on physical positions, eQTL, and chromatin interactions, were associated with AD‐related traits in the literature. For example, the KDM2B gene from the genomic locus (rs9795600, P‐value = 1.13e‐08) was previously associated with AD (Gouveia et al., 2022). For R2, 13 mapped genes were associated with AD‐related traits. For example, the TESC gene from the genomic locus (rs77956314, P‐value = 9.99e‐29) was associated with neurofibrillary tangles measurement, which is formed by hyperphosphorylation of a microtubule‐associated protein known as tau in AD (Wang et al., 2020).ConclusionOur results confirmed genetic variants previously associated with AD and identified novel genomic loci contributing to this neuroanatomical heterogeneity. Further research is needed to understand these novel loci’s biological pathways and functional consequences.

Role of Neuroimaging in Suspected Dementia Patients: Utilization of Structural Imaging Algorithmic‐Based Diagnosis in Resource Limited Settings

AbstractBackgroundIn 2050, it is estimated that the number of dementia patients in the sub Saharan Africa is expected to reach 5.05 million, an increase of 136% from the previous estimate of 2.14 million. The objectives of the present study were to assess the neuroimaging findings and associated factors in dementia suspected patients.MethodA retrospective survey of the medical records of 121 suspected dementia patients whom presented to the Yehuleshet Specialty Clinic with subjective forgetfulness were reviewed. The study duration was between January 1, 2020 and December 31, 2021. Both descriptive and analytical statistics were used to analyze the data.ResultThe mean age was 70.4 (1SD = 10.3) years. Sixty four (52.9%) participants were age below 70. Male accounted for 57.9%. Hyperlipidemia was the commonest (38%) identified vascular risk factor followed by prevalence of hypertension (32.2%) and diabetes mellitus (22.3%). HIV infection was observed in 3.3%. Low mean serum vitamin D level (below 20ng/mL) was observed in individuals with focal & global cortical atrophy and those with white matter hyperintensity. Fifty two (43%) participants fulfilled the clinical and imaging criteria of vascular cognitive impairment (VCI). Nearly quarter of the patients had imaging evidences of focal or global cortical atrophy. Eleven (9.1%) had imaging evidences of surgical causes of dementia. the presences of comorbid hypertension, previous stroke, and Parkinsonism were independent predictors of vascular dementia.ConclusionThe present study shows high burden of vascular cognitive impairment among individuals suspected of dementia.Furthermore, the presences of comorbid hypertension, previous stroke, and Parkinsonism were independent predictors of vascular dementia.

Total glucosides of peony regulate toll-like receptor to inhibit inflammatory response in diabetic nephropathy

Diabetic nephropathy (DN) is a common chronic disease affecting people’s life. Total glucosides of peony (TGP) regulates TLR4/NF-κB activation. This study aims at investigating the underlying mechanism of TGP in DN treatment. A retrospective analysis of clinical data was conducted to observe periodic acid-silver metheramine (PASM) staining and detect the expression of TLR4 and VEGF in DN. Additionally, rats were injected with Streptozocin (STZ) (30–60 mg) according to the ratio of 45–65 mg/kg to establish DN model. 8 weeks later, rats of experimental group were intraperitoneally injected with TGP. Kidney was collected for HE staining to observe morphological changes. Fibronectin expression was detected by histochemistry and the level of TLR4/NF-κB pathway-related proteins and apoptosis were detected by Western blot. PASM staining revealed focal tubular atrophy and interstitial fibrosis in DN patients. The renal medulla gradually disappeared and infiltration increased in control group, while inflammatory cells decreased in experimental group. The expression of fibronectin, TLR4 and p-p65 was decreased after TGP treatment. TGP treatment significantly decreased fibronectin expression and TGP treatment-induced inhibition of NF-κB signaling enhanced apoptotic activation of HK-2 cells, which was partially reversed by TLR4 and NF-κB inhibitors. TGP can inhibit inflammatory response of DN via regulating TLR4/NF-κB.

Trajectories of white matter degeneration in frontotemporal dementia: new insights using fixel‐based analysis

AbstractBackgroundThe three clinical presentations of frontotemporal dementia (FTD), behavioral‐variant FTD (bvFTD), progressive non‐fluent aphasia (PNFA), and semantic dementia (SD), are caused by abnormal aggregation of protein pathologies and progressive brain atrophy that precede the emergence of clinical symptoms. Neuropathology shows a ‘prion‐like’ propagation along white matter pathways before aggregating in the neuronal cell bodies of the grey matter. The in‐vivo mapping of upstream white matter trajectories of degeneration can improve disease staging and understanding of disease mechanisms in FTD, but longitudinal white matter studies are rare due to methodological challenges. Here, we develop a novel neuroimaging approach to map white matter changes in FTD using fixel‐based analysis (FBA), a new diffusion weighted imaging technique.MethodSixty FTD patients (23 bvFTD, 15 PNFA and 22 SD) were matched with 30 heathy controls. Participants underwent a comprehensive annual clinical assessment and high‐resolution multimodal MRI (median 2 years; range 1‐6 years). Time‐varying changes in white matter fibre density and cross‐section were computed with MRtrix3, FreeSurfer 7.1.1 and Spatiotemporal Linear Mixed Effects models.ResultAll FTD syndromes showed more extensive white matter changes at baseline than previously reported. In bvFTD, atrophy extended posteriorly over time, encroaching in tracts connecting subcortical and motor‐associations regions (Fig 1). In PNFA, baseline left‐lateralized atrophy extended anteriorly and inferiorly and into the contralateral hemisphere, eventually mirroring patterns of atrophy at presentation (Fig 2). In SD, the focal left temporal baseline atrophy extended posteriorly and laterally along the inferior and superior longitudinal fasculi, and involving the right hemisphere with disease progression (Fig 3).ConclusionThe FBA approach enabled the identification of new white matter bundles in FTD, with syndrome‐specific effects and improved biological interpretability compared to traditional tensor imaging methods. Our method can be extended beyond FTD to other neurodegenerative disorders to inform better models of disease staging and provide useful targets for patient stratification and monitoring in trials of disease‐monitoring interventions.

Structure-function correlation of retinal photoreceptors in PRPH2-associated central areolar choroidal dystrophy patients assessed by high-resolution scanning laser imaging and microperimetry.

High Magnification Module (HMM™, Heidelberg Engineering, Heidelberg, Germany) imaging is a novel technique, designed to visualize the retina at a cellular level. To assess the potential of HMM™-based metrics as endpoints for future trials, we evaluated correlations between structural HMM™ cone metrics, spectral-domain OCT (SD-OCT, Heidelberg Engineering, Heidelberg, Germany) and retinal sensitivity on microperimetry (MP, MAIA, CenterVue, Padova, Italy) in healthy subjects and p.(Arg142Trp) PRPH2-associated Central Areolar Choroidal Dystrophy (CACD) patients. We projected a default 10° MP grid on composite HMM™ images and performed automated cone density (CD), intercell distance (ICD) and nearest neighbour distance (NND) analysis at stimuli located at 3° and 5° retinal eccentricity. We manually measured intrasubject outer retinal thickness on SD-OCT in absolute and relative scotomas, located outside of focal atrophy. We included 15 CACD patients and five healthy subjects. We found moderate-to-strong correlations of HMM™ metrics and MP sensitivity at 3° eccentricity from the fovea. We found the outer retina at the locations of absolute scotomas to be statistically significant thinner (p = 0.000003, one-sample t-test), as the outer retinal thickness at locations of relative scotomas. Interestingly, HMM™ metrics of these areas did not differ significantly. We found significant correlations between structural photoreceptors metrics on HMM™ imaging and retinal sensitivity on MP in healthy subjects and CACD patients. A multimodal approach, combining SD-OCT, MP and HMM™ imaging, allows for detailed mapping of retinal photoreceptor integrity and restitution potential, important data that could serve as biomarkers in future clinical trials.

SS OCT and OCT-A Findings in Convalescent Inactive Vogt-Koyanagi-Harada Disease

ABSTRACT Purpose This study aimed to determine predictive factors for low final visual acuity in patients with inactive Vogt-Koyanagi-Harada (VKH) disease using Swept-source OCT and OCT-angiography (OCT-A). Methods We conducted a prospective longitudinal study, including 21 patients (42 eyes), who were followed up for the first 24 months after disease onset. Patients were included at the acute phase and subsequently treated. Sequential qualitative and quantitative changes in OCT and OCT-A were assessed. Analytical statistical methods were employed to determine predictive factors for final visual acuity. Results Structural alterations including focal parafoveal outer nuclear layer atrophy, ellipsoid zone disruption, interdigitation zone disruption, and irregular and thickened retinal pigment epithelium line were observed in 57.1% of eyes at month 3, with no significant improvement over time. The presence of flow voids at months 6, 12, and 24 was significantly associated with low final visual acuity. Serous retnal detachment at presentation emerged as an independent risk factor for structural changes detected by SS-OCT during the first 2 years of the disease. Optic disc edema was predictive factor for both structural SS-OCT and OCT-A changes. Conclusion This study underscores the importance of monitoring flow voids to predict final visual acuity and highlights the impact of serous retinal detachment at presentation on structural changes in patients with inactive VKH disease.

IMPG2-Related Maculopathy

PurposeTo investigate the phenotype, variability and penetrance of IMPG2-related maculopathy. DesignRetrospective observational case series. MethodsClinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling. ResultsTwenty-five individuals with a mono-allelic IMPG2 variant were included, 5 of whom were relatives of patients with IMPG2-associated retinitis pigmentosa. In 17 individuals (median age, 52 years; range, 20-72 years), a distinct maculopathy was present and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best corrected visual acuity (BCVA) was ≥ 20/50 in the better eye (n=15) and 5 patients were asymptomatic. Longitudinal observation (n=8, up to 19 years) demonstrated stable maculopathy (n=3), partial/complete resorption (n=4) or increase (n=1) of the subretinal material, with overall stable vision (n=6). The remaining 8 individuals (median age, 58 years; range, 43-83 years; BCVA ≥ 20/25) showed no manifest maculopathy and were identified through segregation analysis. All 8 were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. Eighteen different variants were detected, 11 of them truncating. Molecular modeling of five missense variants, c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C and c.3193G>A supported the hypothesis that these have a loss-of-function effect. ConclusionsMono-allelic IMPG2 variants may result in haplo-insufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related retinitis pigmentosa may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually associated with moderate visual impairment.

Optical coherence tomography with voxel-based morphometry: a new tool to unveil focal retinal neurodegeneration in multiple sclerosis.

Neurodegeneration is the main contributor to disability accumulation in multiple sclerosis. Previous studies in neuro-ophthalmology have revealed that neurodegeneration in multiple sclerosis also affects the neuro-retina. Optical coherence tomography has been used to measure thinning of retinal layers, which correlates with several other markers for axonal/neuronal loss in multiple sclerosis. However, the existing analytical tools have limitations in terms of sensitivity and do not provide topographical information. In this study, we aim to evaluate whether voxel-based morphometry can increase sensitivity in detecting neuroaxonal degeneration in the retina and offer topographical information. A total of 131 people with multiple sclerosis (41 clinically isolated syndrome, 53 relapsing-remitting and 37 progressive multiple sclerosis) and 50 healthy subjects were included. Only eyes with normal global peripapillary retinal nerve fibre layer thickness and no history of optic neuritis were considered. Voxel-based morphometry and voxel-wise statistical comparisons were performed on the following: (i) patients at different disease stages and 2) patients who experienced the first demyelination attack without subclinical optic neuritis, assessed by visual evoked potentials. Standard parameters failed to discern any differences; however, voxel-based morphometry-optical coherence tomography successfully detected focal macular atrophy of retinal nerve fibre layer and ganglion cell/inner plexiform layer, along with thickening of inner nuclear layer in patients who experienced the first demyelination attack (disease duration = 4.2 months). Notably, the atrophy pattern of the ganglion cell/inner plexiform layer was comparable across disease phenotypes. In contrast, the retinal nerve fibre layer atrophy spread from the optic nerve head to the fovea as the disease evolved towards the progressive phase. Furthermore, for patients who experienced the first neurological episode, the severity of retinal nerve fibre layer atrophy at entry could predict a second attack. Our results demonstrate that voxel-based morphometry-optical coherence tomography exhibits greater sensitivity than standard parameters in detecting focal retinal atrophy, even at clinical presentation, in eyes with no history of optic neuritis and with normal latency of visual evoked potentials. Thinning of the ganglion cell/inner plexiform layer primarily concentrated in nasal perifovea in all disease phenotypes, indicating selective vulnerability of retinal ganglion cells and their perifoveal axons. Conversely, the degree of retinal nerve fibre layer thinning seems to be related to the clinical course of multiple sclerosis. The findings suggest bidirectional neurodegeneration in the visual pathway. Voxel-based morphometry-optical coherence tomography shows potential as a valuable tool for monitoring neurodegeneration on a patient level and evaluating the efficacy of novel neuroprotective treatments.

Increased Resolution of Structural MRI at 3T Improves Estimation of Regional Cortical Degeneration in Individual Dementia Patients Using Surface Thickness Maps.

Objective measurement of regional cortical atrophy in individual patients would be a highly desirable adjunct for diagnosis of degenerative dementias. We hypothesized that increasing the resolution of magnetic resonance scans would improve the sensitivity of cortical atrophy detection for individual patients. 46 participants including 8 semantic-variant primary progressive aphasia (svPPA), seven posterior cortical atrophy (PCA), and 31 cognitively unimpaired participants underwent clinical assessment and 3.0T brain scans. SvPPA and PCA were chosen because there is overwhelming prior knowledge of the expected atrophy pattern. Two sets of T1-weighted images with 0.8 mm3 (HighRes) and conventional 1.0 mm3 (ConvRes) resolution were acquired. The cortical ribbon was segmented using FreeSurfer software to obtain surface-based thickness maps. Inter-sequence performance was assessed in terms of cortical thickness and sub-cortical volume reproducibility, signal-to-noise and contrast-to-noise ratios. For clinical cases, diagnostic effect size (Cohen's d) and lesion distribution (z-score and t-value maps) were compared between HighRes and ConvRes scans. The HighRes scans produced higher image quality scores at 90 seconds extra scan time. The effect size of cortical thickness differences between patients and cognitively unimpaired participants was 15-20% larger for HighRes scans. HighRes scans showed more robust patterns of atrophy in expected regions in each and every individual patient. HighRes T1-weighted scans showed superior precision for identifying the severity of cortical atrophy in individual patients, offering a proof-of-concept for clinical translation. Studying svPPA and PCA, two syndromes with well-defined focal atrophy patterns, offers a method to clinically validate and contrast automated algorithms.

MR-based spatiotemporal anisotropic atrophy evaluation of hippocampus in Alzheimer's disease progression by multiscale skeletal representation.

Increasing evidence has shown a higher sensitivity of Alzheimer's disease (AD) progression by local hippocampal atrophy rather than the whole volume. However, existing morphological methods based on subfield-volume or surface in imaging studies are not capable to describe the comprehensive process of hippocampal atrophy as sensitive as histological findings. To map histological distinctive measurements onto medical magnetic resonance (MR) images, we propose a multiscale skeletal representation (m-s-rep) to quantify focal hippocampal atrophy during AD progression in longitudinal cohorts from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The m-s-rep captures large-to-small-scale hippocampal morphology by spoke interpolation over label projection on skeletal models. To enhance morphological correspondence within subjects, we align the longitudinal m-s-reps by surface-based transformations from baseline to subsequent timepoints. Cross-sectional and longitudinal measurements derived from m-s-rep are statistically analyzed to comprehensively evaluate the bilateral hippocampal atrophy. Our findings reveal that during the early AD progression, atrophy primarily affects the lateral-medial extent of the hippocampus, with a difference of 1.8 mm in lateral-medial width in 2 years preceding conversion (p < .001), and the medial head exhibits a maximum difference of 3.05%/year in local atrophy rate (p = .011) compared to controls. Moreover, progressive mild cognitive impairment (pMCI) exhibits more severe and widespread atrophy in the head and body compared to stable mild cognitive impairment (sMCI), with a maximum difference of 1.21 mm in thickness in the medial head 1 year preceding conversion (p = .012). In summary, our proposed method can quantitatively measure the hippocampal morphological changes on 3T MR images, potentially assisting the pre-diagnosis and prognosis of AD.

Optimization of treatment of vulvar scleroatrophic lichen with using modern laser technologies

Background. Vulvar lichen sclerosus (VLS) is a chronic inflammatory dermatosis, which is characterized by focal skin atrophy of the vulva and mucous membranes. It leads to deformation of the perineum. The prevalence of VLS in children is up to 0.1%, among the adults — 3%. The average age of the first symptoms appearance in girls is 5.4 years, in women — 55.1 years. The diagnosis of VLS is made on the base of anamnesis, assessment of pubertal development, physical examination of the external genitalia, advanced vulvoscopy and vaginoscopy, bacteriological, bacterioscopic and cytological studies of vaginal wet mount, assessment of the hormonal profile. The treatment methods include high-potency steroids as the initial treatment, usage of diode, fractional CO2 and erbium lasers with different wavelengths and injections of platelet-rich plasma to improve the regeneration processes of the affected tissue by improving collagenogenesis, vasculogenesis, production of proteoglycans and glycoproteins.&#x0D; The aim of the study is to compare the effectiveness of photodestruction with a manual diode laser of the Dornier Medilas D LiteBeam, wavelength of 940 nm, minimum power in pulsed mode on the girls’ vulva mucosa with various types of VLS during neutral and preadolescent age. To obtain the results there were analyzed criteria including the size of the lesion after photodestruction therapy, the disappearance of cracks and angiomatosis in the LS area. The objectives of the complex therapy of VLS in girls were elimination of itching, decrease of the inflammatory changes, improvement of the skin and mucosa blood supply, and stimulation of local immunological mechanisms.&#x0D; Materials and methods. The study was conducted on the base of the gynecological department of Russian Children’s Clinical Hospital. The effectiveness of the laser-induced thermotherapy with a wavelength of 940 nm, minimum power in pulsed mode on the vulva of VLS girls of neutral and preadolescent periods as a part of the complex therapy was evaluated. Ninety 5 to 13 year VLS patients took part in the trial. They were divided into 3 groups. The first group included 30 patients (average age 7.5 ± 1.1) with atrophic form of lichen treated with a laser with a wavelength of 940 nm. The second group consisted of 30 patients (average age 6.8 ± 1.3) with erythematous-edematous lichen, who were treated with a laser with a wavelength of 635 nm. The third group included 30 patients (average age 7.3 ± 1.2) with erosive and ulcerative form of VLS, who received high-potency corticosteroids therapy. &#x0D; Results. The treatment results in the three subgroups of VLS patients show a diode laser with a wavelength of 940 nm therapy to be the most effective. After the first treatment course 27 (90%) patients in the first group showed a positive trend with a decrease in itching and burning, pink-color presence in vulva mucousа, a decrease of the skin pigmentation area and an increase in the elasticity of the skin. After 2 courses, 29 (96.7%) patients had positive trend. The second most effective method of treatment is photodestruction with a 635 nm wavelength laser. After the 4 courses (two hospitalisations), 25 (83,3%) patients noted a decrease in itching and in a “tightening” feeling. In 24 (80%) patients there was an improvement in the condition of the mucous membranes of the vulva. Reduction of edema was observed in 23 (76.7%) patients by the time of an examination in 3 weeks after the last therapy course. However, it was not possible to completely restore the mucous membranes of the vulva in patients of this group. The least effective — drug therapy with high-potency steroids. 8 (26.7%) patients noted positive dynamics only by the 4th day therapy, 11 (36,7%) by the time of the 3 weeks after the initial application of the ointment, 12 (40%) by the 2nd month. In 5 (16.7%) patients, the visible condition of the mucous membranes did not change, the number of bleeding ulcers decreased minimally.&#x0D; Conclusions. The results of the trial indicate the high efficiency of laser therapy of VLS in children compared with the topical glucocorticoids treatment. The duration of the therapy and condition of the external genitalia after treatment depends on the histological form and stage of VLS. According to our study, laser therapy contributes to the remission onset in pediatric patients with different types of VLS in the shortest possible time after the photodestruction procedure.

Single-institution Series of Hirayama Disease in North America.

A retrospective chart review. The aims of this study were to review pathophysiology, workup, and treatment for Hirayama disease (HD); and to assess outcomes from a single institution. HD is a rare, painless, cervical myelopathy with distal upper extremity weakness, muscle wasting, and spinal cord atrophy. Disease progression-a consequence of repeat flexion injury-occurs up to 5 years from the initial diagnosis. Single-institution review of pediatric HD patients from 2010 to 2020. Patients (n=10 male, n=2 female) presented in the second decade (14-20y) with painless progressive distal upper extremity weakness and atrophy without sensory loss. Electromyography (n=12) demonstrated denervation in C7-T1 myotomes and flexion/extension magnetic resonance imaging showed focal cord atrophy and anterior displacement of the posterior dura with epidural enhancement in flexion. Treatment included observation and external orthoses (n=9) and anterior cervical discectomy with fusion (n=3). One of the 9 patients managed conservatively experienced further deterioration; no patient who underwent anterior cervical discectomy with fusion progressed. Patients with HD require a multidisciplinary approach to diagnosis and treatment to preserve function. Treatment is preventive and aims to minimize flexion injury by inhibiting motion across involved joints. First-line management is avoidance of neck flexion and use of rigid orthosis; in cases of failed conservative management and/or rapid clinical deterioration, surgical fixation can be offered.

Neuropsychiatric symptoms and imbalance of atrophy in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia is characterized by heterogeneous frontal, insular, and anterior temporal atrophy patterns that vary along left-right and dorso-ventral axes. Little is known about how these structural imbalances impact clinical symptomatology. The goal of this study was to assess the frequency of frontotemporal asymmetry (right- or left-lateralization) and dorsality (ventral or dorsal predominance of atrophy) and to investigate their clinical correlates. Neuropsychiatric symptoms and structural images were analyzed for 250 patients with behavioral variant frontotemporal dementia. Frontotemporal atrophy was most often symmetric while left-lateralized (9%) and right-lateralized (17%) atrophy were present in a minority of patients. Atrophy was more often ventral (32%) than dorsal (3%) predominant. Patients with right-lateralized atrophy were characterized by higher severity of abnormal eating behavior and hallucinations compared to those with left-lateralized atrophy. Subsequent analyses clarified that eating behavior was associated with right atrophy to a greater extent than a lack of left atrophy, and hallucinations were driven mainly by right atrophy. Dorsality analyses showed that anxiety, euphoria, and disinhibition correlated with ventral-predominant atrophy. Agitation, irritability, and depression showed greater severity with a lack of regional atrophy, including in dorsal regions. Aberrant motor behavior and apathy were not explained by asymmetry or dorsality. This study provides additional insight into how anatomical heterogeneity influences the clinical presentation of patients with behavioral variant frontotemporal dementia. Behavioral symptoms can be associated not only with the presence or absence of focal atrophy, but also with right/left or dorsal/ventral imbalance of gray matter volume.

Long-term functional and structural outcomes in X-linked retinoschisis: implications for clinical trials.

X-linked retinoschisis (XLRS) is an inherited retinal disease (IRD) caused by pathogenic mutations in the retinoschisin gene, RS1. Affected individuals develop retinal layer separation, leading to loss of visual acuity (VA). Several XLRS gene therapy trials have been attempted but none have met their primary endpoints. An improved understanding of XLRS natural history and clinical outcomes may better inform future trials. Here, we report the long-term functional and structural outcomes of XLRS and the relevance of RS1 genotypes to the visual prognosis of affected individuals. A retrospective chart review of patients with molecularly confirmed X-linked retinoschisis was performed. Functional and structural outcomes, and RS1 genotype data, were included for analysis. Fifty-two patients with XLRS from 33 families were included in the study. Median age at symptom onset was 5 years (range 0-49) and median follow-up was 5.7 years (range 0.1-56.8). Macular retinoschisis occurred in 103 of 104 eyes (99.0%), while peripheral retinoschisis occurred in 48 of 104 eyes (46.2%), most often in the inferotemporal quadrant (40.4%). Initial and final VA were similar (logMAR 0.498 vs. 0.521; p = 0.203). Fifty of 54 eyes (92.6%) developed detectable outer retinal loss by age 20, and 29 of 66 eyes (43.9%) had focal or diffuse outer retinal atrophy (ORA) by age 40. ORA but not central subfield thickness (CST) was associated with reduced VA. Inter-eye correlation was modest for VA (r-squared = 0.03; p = 0.08) and CST (r-squared = 0.15; p = 0.001). Carbonic anhydrase inhibitors (CAIs) improved CST (p = 0.026), but not VA (p = 0.380). Eight of 104 eyes (7.7%) had XLRS-related retinal detachment (RD), which was associated with poorer outcomes compared to eyes without RD (median final VA 0.875 vs. 0.487; p <0.0001). RS1 null genotypes had greater odds of at least moderate visual impairment at final follow-up (OR 7.81; 95% CI 2.17, 28.10; p = 0.002) which was independent of age at onset, initial CST, initial ORA, or previous RD. Overall, long-term follow-up of XLRS patients demonstrated relatively stable VA, with presenting CST, development of ORA, and null RS1 mutations associated with poorer long-term visual outcomes, indicating a clinically relevant genotype-phenotype correlation in XLRS.

Association between morphologic features of intracranial distal arteries and brain atrophy indexes in cerebral small vessel disease: a voxel-based morphometry study.

Brain atrophy represents a final common pathway for pathological processes in patients with cerebral small vessel disease (CSVD) and is now recognized as a strong independent predictor of clinical status and progression. The mechanism underlying brain atrophy in patients with CSVD is not yet fully comprehended. This study aims to investigate the association of morphologic features of intracranial distal arteries (A2, M2, P2 and more distal) with different brain structures [gray matter volume (GMV), white matter volume (WMV), and cerebrospinal fluid volume (CSFV)]. Furthermore, we also examined whether a correlation existed between these cerebrovascular characteristics and GMV in different brain regions. A total of 39 participants were eventually enrolled. The morphologic features of intracranial distal arteries based on TOF-MRA were extracted and quantified using the intracranial artery feature extraction technique (iCafe). The brain 3D-T1 images were segmented into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) using the "Segment" tool in CAT12 for the voxel-based morphometry (VBM) analysis. Univariable and multivariable linear regression models were used to investigate the relationship between these cerebrovascular features and different brain structures. Partial correlation analysis with a one-tailed method was used to evaluate the relationship between these cerebrovascular features and GMV in different brain regions. Our findings indicate that both distal artery length and density were positively correlated with GM fraction in CSVD patients, regardless of whether univariable or multivariable linear regression analyses were performed. In addition, distal artery length (β = -0.428, p = 0.007) and density (β = -0.337, p = 0.036) were also found to be negative associated with CSF fraction, although this relationship disappeared after adjusting for potential confounders. Additional adjustment for the effect of WMHs volume did not change these results. In subgroup anasysis, we found that participants in the highest distal artery length tertile had significantly higher GM fraction and lower CSF fraction level than participants in the lowest distal artery length tertile. In partial correlation analysis, we also found that these cerebrovascular characteristics associated with regional GMV, especially subcortical nuclear. The morphologic features of intracranial distal arteries, including artery length, density and average tortuosity, measured from 3D-TOF MRA, are associated with generalized or focal atrophy indexes of CSVD.

#5295 SECONDARY MEMBRANOUS NEPHROPATHY WITH IGA DEPOSITS IN A PATIENT WITH PRIMARY CILIARY DYSKINESIA

Abstract Background and Aims Membranous nephropathy and IgA nephropathy are two types of common glomerulonephritis worldwide. There are reports of the coexistence of these glomerulopathies, mostly with mesangial expansion and IgA deposits. Furthermore, primary ciliary dyskinesia is rarely associated to glomerulopathy. Thus, we report a case of a patient with primary ciliary dyskinesia with renal biopsy demonstrating membranous glomerulopathy associated with IgA and IgG deposits exclusively in glomerular basement membrane, without complement deposition. Method Case report. Results A 18 years-old man was referred from the nephropediatric outpatient clinic with subnephrotic hematuria and proteinuria. His medical history included a clinical diagnosis of primary ciliary dyskinesia due to a history of several respiratory infections since birth, asthma, rhinitis and bronchiectasis and a 15 years-old brother with a similar history. He was diagnosed with idiopathic thrombocytopenic purpura at age of one year-old and received prednisone. At 3 years-old he presented with nephrotic syndrome, hematuria and hypertension, and was treated with intravenous methylprednisolone and oral cyclophosphamide for three months. Renal biopsy demonstrated mesangial expansion and thickening of the glomerular basement membrane (GBM), without adequate material for immunofluorescence. Because proteinuria and hematuria persisted, the prednisone dose was increased to 2 mg/kg/day and cyclosporine was started. After 5 years on these medications, persisting with proteinuria, a second biopsy was performed and showed 16 glomeruli, three globally sclerosed and the others with diffuse thickening of the GBM, without other alterations, focal interstitial fibrosis and tubular atrophy and diffuse granular deposits of IgA 1+ and IgG 2+ along the GBM. Cyclosporine and prednisone were discontinued. At age of 18 years-old, he was admitted to adult glomerulonephritis clinic with significant developmental delay (weight 28.6kg and height 1.29m2), no edema and normal arterial blood pressure with RAAS inhibition. Laboratory tests: Hb 8.9 g/dL, serum iron 12 mcg/dL, Creatinine 0.7 mg/dL, albumine 2.3 g/dL. Serologies were negative for syphilis, hepatitis B and C, HIV, ANA and anti-DNA, with normal complement C3, C4 and C1q. Urinalysis revealed proteinuria 1+, hematuria 16.000/mL and proteinuria 1.400 mg/d. CT scan showed symmetrical bronchiectasis in both lungs, with mucoid endobronchial impingement and diffuse bronchial parietal thickening; and chronic post-thrombotic changes with calcified thrombi in the left renal vein, extending into the inferior vena cava. A third renal biopsy was performed showing 38 of 45 (84%) globally sclerosed glomeruli without mesangial matrix changes or capsular adhesions. GBM was thickened with spicules and holes and reactive podocytes. The tubulointerstitial compartment showed moderate atrophy and fibrosis (40-50%). Immunofluorescence microscopy evidenced strong immunoreactivity of IgG 3+/3+, IgA 3+/3+, Kappa 3+/3+ and Lambda 2+/3+, in granular pattern exclusively in GBM, without C3. Electron microscopy showed four sclerosed glomeruli, without deposits. Immunohistochemistry staining for IgG1 2+/3+, and it was negative for PLA2R, NELL-1, THSD7A, Exostosin-1 and 2, IgG 2, IgG3 and IgG4. The patient was maintained with supportive treatment, with RAAS inhibition and SGLT2 inhibitors, without immunosuppression. Conclusion This case highlights the codominance of IgG1 and IgA deposits along the MBG, without proliferation or mesangial deposition and without complement activation, in a patient with membranous nephropathy and primary ciliary dyskinesia, a condition rarely associated with glomerulopathies. Although rare, such renal biopsy findings reinforce the need for a better understanding of the different mechanisms of membranous nephritis, in addition to better understanding and management of treatment in this situation.

#3626 A CASE OF PODOCYTE DISEASE WITH AZOTEMIA FOLLOWING TREATMENT WITH INTRAVENOUS IBANDRONATE

Abstract Background and Aims Bisphosphonate use may induce several types of nephrotoxicity. There are many reports on pamidronate-associated glomerular disease, such as focal segmental glomerulosclerosis and zoledronate-associated acute tubular necrosis. However, there are limited reports on ibandronate-associated nephrotoxicity. Herein, we describe a case of podocyte disease accompanied with azotemia following intravenous administration of ibandronate. Method Case report Results An 88-year-old female was referred to the emergency room due to grade 4 edema that developed 1 month before. The patient was diagnosed with osteoporosis 20 months earlier, for which she received quarterly intravenous administration of ibandronate (3 mg). The last dose was administered 2 weeks ago. The patient had no history of diabetes, hypertension, or chronic kidney disease. Laboratory tests revealed heavy proteinuria with a protein/creatinine ratio (PCR) of 32 and hypoalbuminemia (1.9 g/dL) with elevated serum creatinine (sCr) (1.8 mg/dL). Values of serum complement and electrophoresis were within normal ranges. The renal ultrasonogram was unremarkable. A renal biopsy was performed and light microscopy showed mild mesangial hypercellularity and segmental amorphous collagenous deposition in the glomerulus (Fig. 1-A). The tubules revealed focal marked atrophy and interstitial fibrosis (Fig. 1-B). Immunofluorescence studies were unremarkable. Electron microscopy showed diffuse effacement of foot processes and no electron-dense deposit (Fig. 1-C), consistent with podocyte disease favoring focal segmental glomerulosclerosis. The patient was treated with tacrolimus and fimasartan. Steroid use was spared owing to severe osteoporosis. Three months later, the edema subsided and laboratory findings improved (PCR 0.64, serum albumin 4 g/dL, sCr 1.23 mg/dL). Conclusion Compared to pamidronate and zoledronate, ibandronate is more highly protein-bound with a significantly shorter renal tissue half life, which might explain the rarity of ibandronate-related nephrotoxicity. Contrary to the trend of other bisphosphonates nephropathies, our case showed simultaneous podocyte disease and tubule damage. We recommend close monitoring of proteinuria and renal function for prompt nephrotoxicity detection in patients treated with ibandronate.

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

ObjectiveTo identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. Methods682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. ConclusionsLanguage deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials.