Progressive Atrophy Research Articles

Progression to complete retinal pigment epithelium and outer retinal atrophy (cRORA): post hoc analysis of the GATHER1 trial.

Determine rates of progression of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) to complete retinal pigment epithelium and outer retinal atrophy (cRORA) and rates of progression of drusen to iRORA/cRORA in eyes with geographic atrophy (GA) treated with avacincaptad pegol (ACP). Post hoc analysis of the GATHER1 prospective, randomized, double-masked Phase II/III study that evaluated ACP 2mg vs. sham. Optical coherence tomography (OCT) data from GATHER1 were transferred to the Doheny Image Reading and Research Lab for masked analysis by readers experienced with Classification of Atrophy Meeting (CAM) grading features. Regions of OCT volume scans more than 500µm from the border of GA lesions were evaluated at baseline and at months 6, 12, and 18. Participants with iRORA and/or drusen (≥ 40µm height on OCT) at baseline were included in the analysis. The proportion of eyes progressing from iRORA to cRORA in the ACP 2mg group was 5.0%, 15.0%, and 20.0% at months 6, 12, and 18 respectively, as compared with 11.8%, 30.2%, and 41.8% of eyes in the sham group. The proportion of ACP 2mg-treated eyes progressing from drusen to iRORA or cRORA was 3.8%, 7.6%, and 7.6% at months 6, 12, and 18 compared with 15.9%, 18.1%, and 27.2% of sham-treated eyes. Rates of progression from iRORA to cRORA and drusen to iRORA/cRORA were reduced in eyes treated with ACP 2mg vs. sham, with increasing separation between groups over time, suggesting early intervention may slow disease progression. ClinicalTrials.gov identifier: NCT02686658. Date of registration: February 16, 2016. What is known Geographic atrophy is an advanced form of age-related maculardegeneration (AMD) that leads to irreversible vision loss, presenting a significant public health unmet need. The Classification of Atrophy Meeting (CAM) group recommended a new nomenclature for advanced AMD lesions, based on the affected anatomical layers on optical coherence tomography. Accordingly, the terms incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA) were introduced (Guymer et al., Ophthalmology 127:394-409, 2020; Sadda et al., Ophthalmology 125:537-548, 2018). What is new GATHER1 post hoc analysis shows that treatment with avacincaptad pegol (ACP) 2mg decreases the proportion of eyes that progress from iRORA to cRORA, and from drusen to iRORA or cRORA, compared with sham, over 6, 12, and 18months. These findings suggest a potential role for ACP in delaying the progression of existing pre-atrophic AMD lesions.

Increased Survival in Contemporary Parkinson's Disease - a 47 year autopsy study.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The main clinical features are: bradykinesia, rigidity and resting tremor. Other neurodegenerative disorders such as progressive supranuclear palsy and multiple system atrophy share some of these clinical manifestations. All those disorders are collectively known as parkinsonism or Parkinson syndrome (PS). Definite diagnosis of PD requires brain autopsy. There is no known cure for PD. Since its discovery in the 1960s, levodopa (LD) has remained the best and most widely used medication in PD. The impact of that is important to understanding the neuroepidemiology of PD. The incidence of PD rises with advancing age. In the last six decades, life expectancy in the general population has increased resulting in a larger pool of at-risk persons. Onset age of PD is the most reliable indicator of PD survival, as older onset cases have shorter survival. We report on survival in autopsy-confirmed PD cases with onset-age <70 years treated with LD and compare that with similar onset age cases of PD before the discovery of LD. The Saskatchewan Movement Disorders Program (SMDP) has operated uninterrupted since 1968. Long follow-up and autopsy studies are a special interest of the SMDP. All PS cases followed by the SMPD during 47 years (1968-2015) that came to autopsy were considered. Those with autopsy-confirmed PD and onset <70 years were included and were compared with pre-LD cases of similar age of onset. 392 PS cases were seen in our clinic between 1968-2015 and had brain pathology studies. 314 (80%) of those had PD. 128 (41%) of the PD cases had onset <70 years and were included in this study. Their median survival was 18 years. Prior to widespread use of LD, nearly all PD cases had onset <70 years and mean survival was 9.4 years. Longer survival in our study is attributed primarily to modern treatment. Increased survival has resulted in a larger number of older, chronically treated, higher comorbidity, and complicated PD patients. These changes present new challenges. It requires a larger and increasingly diverse workforce for patient care and research.

Alcohol Consumption and Risk of Age-Related Macular Degeneration and Geographic Atrophy Progression: AREDS2 Report 34.

To examine potential relationships between alcohol consumption and age-related macular degeneration (AMD) progression, including progression to late AMD and geographic atrophy (GA) enlargement rate. Post hoc analysis of cohorts within the Age-Related Eye Diseases Study 2 (AREDS2). 6670 eyes (of 3673 participants) with no late AMD at baseline; 1143 eyes (of 841 participants) with GA at ≥2 consecutive visits. Color fundus photographs were collected at annual study visits and graded centrally for late AMD, GA area, and GA proximity. Alcohol consumption was calculated by food frequency questionnaire. Regression analyses of disease progression were performed according to alcohol consumption. Progression to late AMD and its subtypes; GA area-based progression; GA proximity-based progression. Over mean follow-up of 3.8 years, 40.2% of eyes progressed to late AMD. In men, with alcohol tertile 1 (no regular consumption) as reference, hazard ratios for progression to late AMD were 0.69 (95% CI 0.55-0.87, p=0.0015) for tertile 2 and 0.85 (0.71-1.02, p=0.079) for tertile 3. In women, hazard ratios were 1.12 (0.95-1.31, p=0.17) and 0.85 (0.72-1.00, p=0.046), respectively. Over mean follow-up of 3.1 years, GA area-based progression was significantly faster in women than men, at 0.295 (95% CI 0.278-0.311) and 0.260 mm/year (0.241-0.279), respectively (p=0.007). In men, area-based progression differed significantly by alcohol tertile (p=0.0001), at 0.275 (0.248-0.303), 0.183 (0.143-0.223), and 0.280 mm/year (0.254-0.306) in tertiles 1-3, respectively. In women, the area-based rate did not differ significantly by alcohol tertile (p=0.11). In men only, CDC-defined heavy drinking was associated with faster progression (p=0.024), at 0.306 (0.262-0.349) vs 0.252 mm/year (0.233-0.270). In 808 eyes with non-central GA, GA proximity-based progression did not differ significantly by alcohol tertile (p=0.55). Moderate alcohol consumption is associated with decreased risk of progression to late AMD in men. GA progression is faster in women, but its relationship with alcohol consumption is much stronger in men. In men, moderate consumption is associated with slower GA progression and higher consumption with faster progression. Although some of these associations may also relate to confounding, they might suggest that individuals with GA should avoid high alcohol consumption.

A WFS1 variant disrupting acceptor splice site uncovers the impact of alternative splicing on beta cell apoptosis in a patient with Wolfram syndrome.

Wolfram syndrome 1 (WS1) is an inherited condition mainly manifesting in childhood-onset diabetes mellitus and progressive optic nerve atrophy. The causative gene, WFS1, encodes wolframin, a master regulator of several cellular responses, and the gene's mutations associate with clinical variability. Indeed, nonsense/frameshift variants correlate with more severe symptoms than missense/in-frame variants. As achieving a genotype-phenotype correlation is crucial for dealing with disease outcome, works investigating the impact of transcriptional and translational landscapes stemming from such mutations are needed. Therefore, we sought to elucidate the molecular determinants behind the pathophysiological alterations in a WS1 patient carrying compound heterozygous mutations in WFS1: c.316-1G>A, affecting the acceptor splice site (ASS) upstream of exon 4; and c.757A>T, introducing a premature termination codon (PTC) in exon 7. Bioinformatic analysis was carried out to infer the alternative splicing events occurring after disruption of ASS, followed by RNA-seq and PCR to validate the transcriptional landscape. Patient-derived induced pluripotent stem cells (iPSCs) were used as an in vitro model of WS1 and to investigate the WFS1 alternative splicing isoforms in pancreatic beta cells. CRISPR/Cas9 technology was employed to correct ASS mutation and generate a syngeneic control for the endoplasmic reticulum stress induction and immunotoxicity assays. We showed that patient-derived iPSCs retained the ability to differentiate into pancreatic beta cells. We demonstrated that the allele carrying the ASS mutation c.316-1G>A originates two PTC-containing alternative splicing transcripts (c.316del and c.316-460del), and two open reading frame-conserving mRNAs (c.271-513del and c.316-456del) leading to N-terminally truncated polypeptides. By retaining the C-terminal domain, these isoforms sustained the endoplasmic reticulum stress response in beta cells. Otherwise, PTC-carrying transcripts were regulated by the nonsense-mediated decay (NMD) in basal conditions. Exposure to cell stress inducers and proinflammatory cytokines affected expression levels of the NMD-related gene SMG7 (>twofold decrease; p<0.001) without eliciting a robust unfolded protein response in WFS1 beta cells. This resulted in a dramatic accumulation of the PTC-containing isoforms c.316del (>100-fold increase over basal; p<0.001) and c.316-460del (>20-fold increase over basal; p<0.001), predisposing affected beta cells to undergo apoptosis. Cas9-mediated recovery of ASS retrieved the canonical transcriptional landscape, rescuing the normal phenotype in patient-derived beta cells. This study represents a new model to study wolframin, highlighting how each single mutation of the WFS1 gene can determine dramatically different functional outcomes. Our data point to increased vulnerability of WFS1 beta cells to stress and inflammation and we postulate that this is triggered by escaping NMD and accumulation of mutated transcripts and truncated proteins. These findings pave the way for further studies on the molecular basis of genotype-phenotype relationship in WS1, to uncover the key determinants that might be targeted to ameliorate the clinical outcome of patients affected by this rare disease. The in silico predicted N-terminal domain structure file of WT wolframin was deposited in the ModelArchive, together with procedures, ramachandran plots, inter-residue distance deviation and IDDT scores, and Gromacs configuration files (doi/10.5452/ma-cg3qd). The deep-sequencing data as fastq files used to generate consensus sequences of AS isoforms of WFS1 are available in the SRA database (BioProject PRJNA1109747).

Successful Management of Parry-Romberg Syndrome With Lipografting: A Case Report

Parry-Romberg Syndrome (PRS), or progressive hemifacial atrophy, is a rare disorder marked by the progressive atrophy of skin and soft tissues, sometimes affecting muscles, cartilage, and bones. Typically manifesting in childhood, PRS has a 66% female predilection and sporadic occurrence. Diagnosis is clinical, supplemented by tests to exclude other conditions. Treatment options include bone/cartilage grafts, fat grafts, dermal fillers, and free tissue transplantation. Lipoinjection, using autologous adipose tissue enriched with stem cells, is a promising technique. A 33-year-old female with PRS exacerbated by pregnancy presented with severe right hemifacial atrophy. Initial lipoinjection elsewhere resulted in significant graft reabsorption. At our institution, a second lipoinjection was performed at age 34 after disease remission. Five months postoperatively, 30% graft reabsorption was noted, but significant improvement in facial symmetry was achieved. A second lipoinjection session further enhanced facial volume and skin quality. Four months postoperatively, the patient showed substantial improvement, with 90% facial symmetry and stable disease remission. Autologous lipoinjection is an effective treatment for PRS-related facial atrophy, offering minimal tissue rejection and satisfactory aesthetic outcomes. The presented case highlights the potential of this technique in achieving significant clinical improvement and facial symmetry in PRS patients.

Spinal cord evaluation in multiple sclerosis: clinical and radiological associations, present and future

Abstract Spinal cord disease is important in most people with multiple sclerosis (MS) but assessment remains less emphasized in patient care, basic and clinical research, and therapeutic trials. The North American Imaging in Multiple Sclerosis (NAIMS) Spinal Cord Interest Group formed to determine and present the contemporary landscape of MS spinal cord evaluation, further existing and advanced spinal cord imaging techniques, and foster collaborative work. Important themes arose: 1) Multiple Sclerosis Spinal Cord Lesions (differential diagnosis, association with clinical course); 2) Spinal Cord Radiological-Pathological Associations; 3) “Critical” spinal cord lesions; 4) Multiple Sclerosis Topographical Model; 5) Spinal Cord Atrophy; 6) Automated and Special Imaging Techniques. Distinguishing multiple sclerosis from other myelopathic etiology is increasingly refined by imaging and serological studies. Postmortem spinal cord findings and MRI-pathological correlative studies demonstrate MRI’s high sensitivity detecting microstructural demyelination and axonal loss. Spinal leptomeninges include immune inflammatory infiltrates, some in B-cell lymphoid-like structures. “Critical” demyelinating lesions along spinal cord corticospinal tracts are anatomically consistent with and may be disproportionately associated with motor progression. Multiple Sclerosis topographical model implicates the spinal cord as an area where threshold impairment associates with multiple sclerosis disability. Progressive spinal cord atrophy and “silent” multiple sclerosis progression may be emerging as an important multiple sclerosis prognostic biomarker. Manual atrophy assessment is complicated by rater bias, while automation (e.g. Spinal Cord Toolbox), and artificial intelligence may reduce this. Collaborative research by NAIMS and similar groups with experts combining distinct strengths is key to advancing assessment and treatment of people with multiple sclerosis spinal cord disease.

Anti-Ma-2 associated encephalitis presenting as slowly progressive dementia and cerebellar atrophy

Abstract Cognitive impairment can be a manifestation of a neurodegenerative disease or may have a reversible etiology. Among reversible causes, metabolic, nutritional and autoimmune conditions are commonly evaluated. We report 43-year-old lady who presented with history of personality changes first noted three years back. Subsequently, she developed slowness in speech and activities of her daily living, hypersomnolence, dream enactment, unexplained weight gain and memory impairment. Cognitive assessment revealed poor delayed recall, impaired copying, calculation deficits and bradyphrenia. Mild bradykinesia and rigidity of upper limbs were also noted. MRI brain showed minimal cerebral atrophy and gross cerebellar atrophy. Blood investigation revealed strongly positive anti Ma-2 antibodies. Whole body PET-CT was negative. Ma-2 encephalitis is characterised by diencephalic, brainstem and /or limbic involvement. Presence of Ma-2 antibodies has strong link with malignancies, commonest being the testicular cancer. Anti- neuronal antibodies in association with progressive cognitive impairment in the absence of encephalitis like picture is increasingly being recognized. Although autoimmune work up is generally advocated for rapidly progressive dementia, this case highlights the need to consider antineuronal antibody evaluation in a young individual with longer duration of symptoms.

SMN depletion impairs skeletal muscle formation and maturation in a mouse model of SMA.

Spinal muscular atrophy (SMA) is characterized by low levels of the ubiquitously expressed Survival Motor Neuron (SMN) protein, leading to progressive muscle weakness and atrophy. Skeletal muscle satellite cells play a crucial role in muscle fiber maintenance, repair, and remodelling. While the effects of SMN depletion in muscle are well documented, its precise role in satellite cell function remains largely unclear. Using the Smn2B/- mouse model, we investigated SMN-depleted satellite cell biology through single fiber culture studies. Myofibers from Smn2B/- mice were smaller in size, shorter in length, had reduced myonuclear domain size, and reduced sub-synaptic myonuclear clusters-all suggesting impaired muscle function and integrity. These changes were accompanied by a reduction in the number of myonuclei in myofibers from Smn2B/- mice across all disease stages examined. Although the number of satellite cells in myofibers was significantly reduced, those remaining retained their capacity for myogenic activation and proliferation. These findings support the idea that a dysregulated myogenic process could be occurring as early in muscle stem cells during muscle formation and maturation in SMA. Targeting those pathways could offer additional options for combinatorial therapies for SMA.

A novel management challenge in age-related macular degeneration: Artificial intelligence and expert prediction of geographic atrophy

PurposeThe progression of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is highly variable among individuals. Prediction of the progression is critical to identify patients who will benefit most from the first treatments currently approved. The aim of this study was the investigation of the value and difference in predictive power between ophthalmologists and artificial intelligence (AI) to reliably assess individual speed of GA progression. DesignProspective, expert and AI comparison study. ParticipantsEyes with natural progression of GA from a prospective study (NCT02503332). MethodsOphthalmologists predicted yearly growth speed of GA, as well as selecting the potentially faster growing lesions from two eyes based on fundus autofluorescence (FAF), near-infrared reflectance (NIR), and optical coherence tomography (OCT). A deep learning algorithm predicted progression solely on the baseline OCT (Spectralis, Heidelberg Engineering, Germany). Main Outcome MeasuresAccuracy, weighted kappa (κ), and concordance index (c-index) between the prediction made by ophthalmology specialists, ophthalmology residents and the AI. ResultsA total of 134 eyes of 134 patients from a phase II clinical trial were included, among those 53 were from the sham arm and 81 from untreated fellow eyes. 2880 gradings were performed by four ophthalmologists. Human experts reached an accuracy of 0.37, 0.43, 0.41 and a κ of 0.06, 0.16, 0.18 on FAF, NIR+OCT and FAF+NIR+OCT, respectively. On a pairwise comparison task, human experts achieved a c-index of 0.62, 0.59 and 0.60. Automated AI-based analysis reached an accuracy of 0.48 and a κ of 0.23 on the first task, and a c-index of 0.69 on the second task solely utilizing OCT imaging. ConclusionsPrediction of individual progression will become an important task for patient counseling, most importantly with treatments becoming available. Human gradings improved with the availability of OCT. However, automated AI performed better than ophthalmologists in several comparisons. AI-supported decisions improve clinical precision, access to timely care for the community, and socioeconomic feasibility in the management of the leading cause for irreversible vision loss.

Type-1 spinal muscular atrophy cohort before and after disease-modifying therapies.

Spinal muscular atrophy (SMA-5q) is a neurodegenerative disease characterized by progressive muscle atrophy, hypotonia, and weakness, with SMA 1 presenting symptoms within the first 6 months of life. Disease-modifying therapies have been approved, with better outcomes with earlier treatment. To describe the safety and clinical efficacy of disease-modifying therapies based on SMN1 and SMN2 gene strategies concerning motor, respiratory, and bulbar function. Patients with SMA 1 were divided into 2 groups: those exclusively on nusinersen (group 1) and those transitioning to onasemnogene abeparvovec (OA) (group 2). Over 18 months, patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale, developmental milestones, ventilation needs and duration, nutritional support needs, consistency of food, and signs of dysphagia. There were ten patients, divided between the groups; in group 1, the average age for starting nusinersen was 53.6 (12-115) months, and, in group 2, the age was 7 (1-12) months for nusinersen and 15.2 (10-19) months for OA. Our results indicate that 70% of patients reached some motor milestones, with group 1 increasing by 10.2 points on the CHOP-INTEND scale, while group 2 increased by 33 points. Additionally, 90% of the patients experienced no respiratory decline, and 30% maintained oral feeding. No serious adverse effects or deaths were recorded. Both groups showed improvement in motor function and stabilization of respiratory and bulbar function, with the difference between the groups possibly being related to the earlier treatment initiation. Thus, the present study provides valuable insights into the real-world safety and clinical efficacy of disease-modifying therapies for SMA 1 patients.

Causal role of immune cells in muscle atrophy: mendelian randomization study

Immune system and inflammation had a great influence on the progression of muscle atrophy. However, the causal relationship with specific immune cell traits remained uncertain. The aim of this study was to elucidate the genetic influences on these associations, providing insights into the underlying mechanisms of muscle atrophy. A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal relationship between immune cell phenotypes and muscle atrophy. Data on immune cell phenotypes were obtained from a research cohort containing data on 731 immune cell phenotypes and data on muscle atrophy were sourced from a Finnish database. MR analysis was performed using the MR-Egger method, weighted median, inverse variance weighting, heterogeneity testing, sensitivity analysis, and multiplicity analysis, with results subjected to false discovery rate(FDR) correction. Additionally, the UK Biobank cohort was utilized as an external validation. A total of 31 immune phenotypes with causal relationships with muscle atrophy were identified, including various phenotypes of conventional dendritic cells, myeloid cells, T cells/B cells/natural killer cells, regulatory cells, and T cell maturation stages. Among them, 12 immune phenotypes were identified as exhibiting a positive causal relationship with muscle atrophy, while 19 immune phenotypes were demonstrated to have a negative causal association, highlighting the complex interactions between immune cells and muscle health. The results of the reverse MR analysis indicated that a negative correlation between muscle atrophy and CD28 on secreting Treg (OR = 0.9038, 95%CI:0.8308 ~ 0.9832, P = 0.0186). A significant positive correlation was revealed by external datasets between the CD25 on IgD + CD38- immune phenotype and the risk of muscle atrophy, which was consistent with the trend observed in the training group (OR = 1.1041, 95% CI: 1.1005–1.1076, P = 0.0263). No evidence of pleiotropy was observed, and the reliability of these findings was demonstrated by the leave-one-out analysis. The findings highlight significant correlations between certain immune cell features and muscle atrophy, providing potential targets for further investigation of immunological mechanisms and therapeutic interventions for this condition.

Age-related macular degeneration: natural history revisited in geographic atrophy.

Progression of geographic atrophy varies significantly based on individual and lesion characteristics. Much research has strived to understand prognostic indicators of lesion progression over time, yet integrating findings to date may pose a challenge to clinicians. This review strives to synthesize current knowledge on genetic, behavioral, structural, and functional factors that influence geographic atrophy across the lifetime. Further, it highlights how vision-related quality of life allows for a more holistic appraisal of the impact of geographic atrophy on everyday functioning. The ultimate aim of this paper is to aid clinicians in counseling patients on medical management as well as providing accurate disease prognostication tailored to the individual patient.

Efficacy of Nusinersen Treatment in Type 1, 2, and 3 Spinal Muscular Atrophy: Real-World Data from a Single-Center Study

Background: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease characterized by progressive muscle weakness and atrophy due to the absence of the survival motor neuron 1 (SMN1) gene. SMA is classified into types 0 through 4 based on the age of symptom onset and the severity of motor function decline. Recent advances in SMA treatment, including nusinersen, onasemnogene abeparvovec, and risdiplam, have significantly improved the prognosis of SMA patients. This study evaluated the safety and efficacy of nusinersen in pediatric patients with SMA types 1, 2, and 3 in a real-world clinical setting. Methods: This prospective observational single-center study assessed the treatment effects of nusinersen in 23 pediatric patients with genetically confirmed SMA over a 22-month observation period. All the participants received intrathecal loading doses of 12 mg of nusinersen on days 1, 14, 28, and 63, followed by maintenance doses every four months. Functional assessments were conducted using the CHOP-INTEND scale. Data were collected during routine patient visits, including clinical laboratory tests and vital sign parameters, and adverse events were recorded. The inclusion criteria were defined by the national reimbursement program for nusinersen treatment in Poland. Results: Initially, 37 patients ranging from 1 month old to 18 years old were included, but 23 were ultimately observed due to changes in treatment regimens or assessment scales. The patients showed significantly improved CHOP-INTEND scores over the 22-month period. At 6 months, the average increase was 4.2 points, continuing to 17.8 points at 22 months. By the end of the study, 100% of patients showed either stabilization or improvement, with significant clinical improvements observed in several patients. Nusinersen was generally well-tolerated, with post-lumbar puncture headache and lower back pain being the most common adverse events. Conclusions: Nusinersen treatment significantly enhances motor function in pediatric patients with SMA types 1, 2, and 3. This study demonstrates the importance of early and sustained treatment, with most patients showing the continuous improvement or stabilization of motor function. These findings support the use of nusinersen as an effective therapy for SMA; however, further research is needed to understand the long-term outcomes and optimize treatment strategies.

Photobiomodulation as a Potential Treatment for Alzheimer’s Disease: A Review Paper

Background: Alzheimer’s disease (AD), the most prevalent form of dementia, is a leading neurodegenerative disorder currently affecting approximately 55 million individuals globally, a number projected to escalate to 139 million by 2050. Despite extensive research spanning several decades, the cure for AD remains at a developing stage. The only existing therapeutic options are limited to symptom management, and are often accompanied by adverse side effects. The pathological features of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, result in progressive neuronal death, synaptic loss, and brain atrophy, leading to significant cognitive decline and a marked reduction in quality of life. Objective: In light of the shortcomings of existing pharmacological interventions, this review explores the potential of photobiomodulation (PBM) as a non-invasive therapeutic option for AD. PBM employs infrared light to facilitate cellular repair and regeneration, focusing on addressing the disease’s underlying biomechanical mechanisms. Method: This paper presents a comprehensive introduction to the mechanisms of PBM and an analysis of preclinical studies evaluating its impact on cellular health, cognitive function, and disease progression in AD.The review provides a comprehensive overview of the various wavelengths and application methods, evaluating their efficacy in mitigating AD-related symptoms. Conclusions: The findings underscore the significant potential of PBM as a safe and effective alternative treatment for Alzheimer’s disease, emphasizing the necessity for further research and clinical trials to establish its therapeutic efficacy conclusively.

Adult-onset neuronal ceroid lipofuscinosis misdiagnosed as autoimmune encephalitis and normal-pressure hydrocephalus: A 10-year case report and case-based review.

Neuronal ceroid lipofuscinoses (NCLs) are rare, fatal, inherited neurodegenerative disorders characterized by myoclonic epilepsy, cognitive decline, brain atrophy, and retinopathy. The pathogenesis and clinical manifestations of NCL are not well understood and frequently result in misdiagnosis and overtreatment. The aim of this case report and review is to improve our understanding of the clinical features and management of NCL. A 36-year-old woman initially presented with refractory epilepsy. Initially diagnosed with autoimmune encephalitis, the patient was later diagnosed with normal-pressure hydrocephalus. A definitive diagnosis of adult-onset neuronal ceroid lipofuscinosis (ANCL) was established after 10 years of observation, utilizing biopsy and genetic testing. High-dose intravenous immunoglobulin and methylprednisolone were administered, along with the insertion of a ventriculoperitoneal shunt. Despite various treatments, the patient's condition did not improve. ANCL typically presents with the clinical triad of refractory seizures, progressive cognitive decline, and movement disorders. Neuroimaging often reveals progressive brain atrophy on magnetic resonance imaging, while electroencephalograms frequently show epileptiform discharges. The prognosis is generally poor. Improved understanding of ANCL from both clinical and radiological perspectives, coupled with early consideration of differential diagnoses, could minimize unnecessary interventions and optimize patient care.

Geographic atrophy progression secondary to age-related macular degeneration: Five years of follow-up.

To study the progression of geographic atrophy (GA) secondary to age-related macular degeneration over a five-year follow-up. Eyes with GA included to assess demographic data, yearly optical coherence tomography (OCT) findings and the GA growth rate on infra-red (IR) images. A total of 41 eyes of 29 patients were included with a mean age of 81.76 ± 6.37 at baseline, and 65.51% were females. Over five years, there was a significant increase in the mean GA area from 8.44 ± 8.98 mm² to 13.32 ± 10.07 mm² (P < 0.001), with an annual growth rate of 1.14 ± 0.78 mm². The annual growth rates in females were slightly higher compared to males (1.29 ± 0.89 mm2 vs 0.96 ± 0.49 mm2, p = 0.569), and in smokers was slightly higher than non-smokers (1.35 ± 0.85 mm2 vs 0.94 ± 0.66 mm2, p = 0.100). Larger GA areas at the baseline showed higher GA progression in mm2 per year (P = 0.04). Smaller GA areas and fovea-spared GA at the baseline exhibited a larger percentage increase (P < 0.001 and P = 0.015, respectively). There was a lower GA progression rate in eyes with outer retinal tubulations (ORT) (P = 0.027), yet no significant correlation was found between GA progression and other OCT features. Smaller, fovea-sparing GA eyes experienced a more substantial proportional increase over five years. Also, The presence of ORT was associated with a slower rate of GA progression. Additionally, we observed a trend of faster GA growth in smokers and female genders.

MicroRNAs as Biomarkers in Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by the loss of the survival motor neuron (SMN) protein, leading to degeneration of anterior motor neurons and resulting in progressive muscle weakness and atrophy. Given that SMA has a single, well-defined genetic cause, gene-targeted therapies have been developed, aiming to increase SMN production in SMA patients. The SMN protein is likely involved in the synthesis of microRNAs (miRNAs), and dysregulated miRNA expression is increasingly associated with the pathophysiology of SMA. Currently, there is a lack of reliable biomarkers to monitor SMA; therefore, the search for novel SMA biomarkers, including miRNAs, is crucial as reliable tools are needed to track disease progression, predict the response to therapy and understand the different clinical outcomes of available treatments. In this review, we compile data on miRNAs associated with SMA pathogenesis and their potential use as biomarkers. Based on current knowledge, the most frequently deregulated miRNAs between SMA patients and controls, as well as pre- and post-treatment in SMA patients, include miR-1-3p, miR-133a-3p, miR-133b, and miR-206. These findings offer promising possibilities for improving patient classification and monitoring disease progression and response to treatment. Additionally, these findings provide insights into the broader molecular mechanisms and networks of SMA that could inform the development of future therapeutic strategies.

Delayed-onset cord1 progressive retinal atrophy in English Springer Spaniels genetically affected with the RPGRIP1 variant.

Cone-rod dystrophy (cord1) is a form of progressive retinal atrophy. It is linked to an RPGRIP1 genetic variant which is the third most common canine disease variant thus far. While the variant affects various breeds, it is highly prevalent in English Springer Spaniels (ESSs). Yet its clinical and pathological implications remain equivocal. Herein, we study the retinal phenotype in ESSs genetically affected with the RPGRIP1 variant. Over 4 years, 494 ESSs (123 affected) were enrolled. Owner-perceived vision was collected via a questionnaire. Ophthalmic examination included fundus photography. In selected ESSs, retinal function and structure were assessed using electroretinography (ERG, 148 dogs) and optical coherence tomography (OCT, 4 dogs). Ophthalmoscopic changes included peripheral hypo-reflective lesions often with distinct borders progressing centripetally culminating in generalized retinal atrophy. Cross-sectional study revealed declining photopic ERG amplitudes with age in the affected group but not in controls. OCT indicated progressive photoreceptor loss. Despite ophthalmoscopic, ERG, or OCT abnormalities, most affected dogs were not visually impaired per their owners. In a fraction of afflicted ESSs, vision/globe-threatening complications were documented including cataracts, lens luxation, and glaucoma. In ESSs, the RPGRIP1 variant is associated with insidious pathology with delayed-onset visual defects. The subtle phenotype without apparent visual deficit until the final years of life, if at all, may have caused underdiagnosis of cord1. Still, DNA testing remains informative, and ERG and OCT indicate progressive pathology. Peripheral fundus examination and photopic ERG are particularly useful for early detection and monitoring of cord1.

New Onset Refractory Status Epilepticus with diffuse cerebral restricted diffusion in young children; a novel clinical-radiologic presentation

New-onset refractory status epilepticus (NORSE) is a clinical presentation characterized by explosive-onset refractory status epilepticus (RSE) without evident etiology or active epilepsy, often leading to devastating epilepsy. There is heterogeneity in neuroradiographic findings for NORSE. We encountered a series of young patients with NORSE who had diffuse cerebral restriction in diffusion (DCRD) with similar radiographic appearances as acute encephalopathy with biphasic seizures and late restricted diffusion/acute leukoencephalopathy with restricted diffusion (AESD/ALERD). We explore clinical similarities and proposed pathophysiologic overlaps to highlight a novel clinical-radiologic presentation. Retrospective review was completed for patients younger than five years meeting NORSE criteria and then screened for radiographic evidence of DCRD. Demographic, clinical, and outcome data were collected. Eleven patients met NORSE criteria, of whom seven displayed DCRD. Immunosuppressant management varied. All patients required multiple antiseizure medications and continuous infusions for RSE. Only one had an etiology identified (genetic). All but one patient developed diffuse, global, and progressive cerebral atrophy. Two patients died: one after prolonged seizure three years post-NORSE and another of unknown causes two months post-NORSE. Of five survivors, three have medically refractory epilepsy. Most survivors have severe disability. We present a single-center case series of seven patients with NORSE and DCRD, akin to AESD/ALERD. Our patients differed clinically to AESD/ALERD in terms of seizure severity and poorer outcome. There is a need to develop biomarkers for specific NORSE phenotypes. The young child with NORSE and DCRD may represent a novel phenotype with a specific neuroradiographic signature that deserves further attention.

Nerve ultrasound in amyotrophic lateral sclerosis: systematic review and meta-analysis

Background/ AimAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, causing progressive atrophy of muscles, hypertonia, and paralysis. This study aimed to evaluate the current evidence and effectiveness of ultrasound in investigating nerve cross-sectional area (CSA) of peripheral nerves, vagus and cervical roots in those with ALS compared with healthy controls and to pool the CSA measurements.MethodsA systematic search was conducted on Cochrane, Clarivate Web of Science, PubMed, Scopus, and Embase for the mesh terms nerve, ultrasonography, and amyotrophic lateral sclerosis. A quality assessment was performed using the New-Ottawa scale. In addition, a double-arm meta-analysis using Review Manager 5 software version 5.4 was performed.ResultsFrom the seventeen studies included in this review, the overall mean difference showed that individuals with ALS had a significantly smaller CSA in comparison to healthy controls for median, ulnar, C6 root, and phrenic nerves. However, no significant difference in the CSA was found in radial, vagal, sural, and tibial nerves.DiscussionThis study confirmed results of some of the included studies regards the anatomic sites, where nerve atrophy in ALS could be detected to potentially support the diagnosis of ALS. However, we recommend further large, prospective studies to assess the diagnostic value of these anatomical sites for the diagnosis of ALS.ConclusionsOur findings confirmed specific anatomic sites to differentiate ALS patients from healthy controls through ultrasound. However, these findings cannot be used to confirm the ALS diagnosis, but rather assist in differentiating it from other diagnoses.Trial registrationRetrospectively registered on July 30th 2024 in PROSPERO (PROSPERO (york.ac.uk)) with ID574702.Graphical abstract