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Introduction/Aims: Severe spinal deformities and previous spinal orthopedic instrumentation may result in substantial technical challenges for nusinersen delivery through lumbar puncture in patients with spinal muscular atrophy (SMA). The aim of this paper was to review our experience with ultrasound‐guided cervical puncture as an alternative approach for the intrathecal administration of nusinersen. Methods: This was a retrospective medical record review of transverse interlaminar ultrasound‐guided C1‐C2 puncture for nusinersen delivery in SMA patients. The details of puncture, complications, and success rate of the procedure were summarized. Results: There were four patients who received a total of 13 cervical punctures for nusinersen delivery. All procedures were technically successful with no major complications. Full doses of nusinersen were delivered intrathecally. Discussion: Transverse interlaminar ultrasound‐guided C1‐C2 puncture is an alternative approach for administering nusinersen if lumbar puncture fails. The success of the technique requires a thorough preprocedural evaluation of cervical spine imaging, sound knowledge of the cervical sonoanatomy and careful manipulation of the needle. [ABSTRACT FROM AUTHOR]

Background and purpose: Spinal muscular atrophy (SMA) as the second most common neurodegenerative disorder in childhood is characterized by the deficiency of survival of motor neuron (SMN) protein leading predominantly to degeneration of alpha motor neurons and consequently to progressive muscle weakness and atrophy. Besides some biomarkers like SMN2 copy number therapeutic biomarkers for SMA with known relevance for neuromuscular transmission are lacking. Here, we examined the potential of Thrombospondin-4 (TSP4) to serve as a cerebrospinal fluid (CSF) biomarker, which may also indicate treatment response. Methods: We used untargeted proteomic analyses to determine biomarkers in CSF samples derived from pediatric pre-symptomatic (n = 6) and symptomatic (n = 4) SMA patients. The identified biomarker TSP4 was then validated in additional 68 CSF samples (9 adult and 24 pediatric SMA patients, 5 adult and 13 pediatric non-disease controls in addition to 17 pediatric disease controls) by enzyme-linked immunosorbent assay (ELISA) as an additional analytical approach. Results: Untargeted proteomic analyses of CSF identified a dysregulation of TSP4 and revealed a difference between pre-symptomatic SMA patients and patients identified after the onset of first symptoms. Subsequent ELISA-analyses showed that TSP4 is decreased in pediatric but not adult SMA patients. CSF of pediatric patients with other neurological disorders demonstrated no alteration of TSP4 levels. Furthermore, CSF TSP4 levels of pediatric SMA patients increased after first dose of Nusinersen. Conclusions: We found that TSP4 levels are exclusively reduced in CSF of pediatric SMA patients and increase after treatment, leading us to the hypothesis that TSP4 could serve as a CSF biomarker with the potential to monitor treatment response in pediatric SMA patients. Moreover, TSP4 enable to distinguish pre-symptomatic and symptomatic patients suggesting a potential to serve as a stratification marker. [ABSTRACT FROM AUTHOR]

Background and objectives: Clinical factors are not sufficient to fix a prognosis of recovery after stroke. Pyramidal tract or alternate motor fiber (aMF: reticulo-, rubrospinal pathways and transcallosal fibers) integrity and remodeling processes assessable by diffusion tensor MRI (DTI) and voxel-based morphometry (VBM) may be of interest. The primary objective was to study longitudinal cortical brain changes using VBM and longitudinal corticospinal tract changes using DTI during the first 4 months after lacunar cerebral infarction. The second objective was to determine which changes were correlated to clinical improvement. Methods: Twenty-one patients with deep brain ischemic infarct with pure motor deficit (NIHSS score ≥ 2) were recruited at Purpan Hospital and included. Motor deficit was measured [Nine peg hole test (NPHT), dynamometer (DYN), Hand-Tapping Test (HTT)], and a 3T MRI scan (VBM and DTI) was performed during the acute and subacute phases. Results: White matter changes: corticospinal fractional anisotropy (FACST) was significantly reduced at follow-up (approximately 4 months) on the lesion side. FAr (FA ratio in affected/unaffected hemispheres) in the corona radiata was correlated to the motor performance at the NPHT, DYN, and HTT at follow-up. The presence of aMFs was not associated with the extent of recovery. Grey matter changes: VBM showed significant increased cortical thickness in the ipsilesional premotor cortex at follow-up. VBM changes in the anterior cingulum positively correlated with improvement in motor measures between baseline and follow-up. Discussion: To our knowledge, this study is original because is a longitudinal study combining VBM and DTI during the first 4 months after stroke in a series of patients selected on pure motor deficit. Our data would suggest that good recovery relies on spared CST fibers, probably from the premotor cortex, rather than on the aMF in this group with mild motor deficit. The present study suggests that VBM and FACST could provide reliable biomarkers of post-stroke atrophy, reorganization, plasticity and recovery. ClinicalTrials.gov Identifier: NCT01862172, registered May 24, 2013 [ABSTRACT FROM AUTHOR]

Background: Deep gray matter (DGM) atrophy and lesions are found in multiple sclerosis (MS). Objective: To optimize automated segmentation for 7 T DGM volumetrics and assess sensitivity to atrophy and relationship to DGM lesions and disability in relapsing–remitting (RR) MS. Methods: 30 RRMS subjects [mean age 44.0 years, median Expanded Disability Status Scale (EDSS) score 2] and 14 healthy controls underwent 7 T MRI with 3D magnetization-prepared 2 rapid gradient-echoes (MP2RAGE) and fluid-attenuated inversion recovery. Customizing an automated pipeline to assess DGM structure volumes required pre-processing combining two MP2RAGE inversion times and uniform T1 images, and noise-suppressed reconstruction. DGM volumes were normalized. Brain DGM lesions and white matter T2 lesion volume (T2LV) were expert-quantified. Spearman correlations and Wilcoxon rank-sum tests were assessed. Results: DGM lesions were found in 77% (n = 23) of MS subjects and no controls, with thalamic lesions most prevalent (73%). An average of 3.6 DGM lesions was found per person with MS. Total DGM volumes were lower in MS vs. controls (p = 0.034), varying by region, most pronounced in the caudate (p = 0.008). DGM volumes inversely correlated with EDSS (total DGM: r = – 0.45, p = 0.014; globus pallidus: r = – 0.42, p = 0.023; putamen: r = – 0.44, p = 0.016; caudate: r = – 0.37, p = 0.047) and T2LV (total DGM: r = – 0.53, p = 0.003; putamen: r = – 0.40, p = 0.030; thalamus: r = – 0.63, p < 0.001). DGM atrophy was most closely linked to disability among all MRI measures. Thalamic lesion volume correlated inversely with thalamic volume (r = – 0.38, p = 0.045). Conclusion: 7 T MRI shows a link between DGM atrophy and both white matter lesions and physical disability in RRMS. Thalamic lesions are associated with thalamic atrophy. [ABSTRACT FROM AUTHOR]

Background: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA. Methods: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson's disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores). Results: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90–1.00; plasma: AUC = 0.90, 95% CI 0.81–1.00). Discussion: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD. [ABSTRACT FROM AUTHOR]

Background: The prognostic impact of dysphagia in multiple system atrophy (MSA) remains controversial. This study aimed to investigate the relationship between dysphagia severity and survival in MSA and to elucidate whether this impact differs between MSA-cerebellar ataxia (MSA-C) and MSA-parkinsonism (MSA-P). Methods: This retrospective study included 297 patients with MSA: 251 met criteria for clinically established MSA and 46 for clinically probable MSA. Among them, 171 had MSA-C and 126 had MSA-P. We evaluated symptomatic dysphagia within 3 years of onset and quantified dysphagia severity using the Hyodo score (0 to 12) through fibreoptic endoscopic evaluation of swallowing (FEES) and clinical features, including autonomic dysfunction and vocal cord paralysis. Patients were followed up until death or tracheostomy, and survival factors were analysed using the log-rank test and multivariate Cox proportional hazards model. Results: Ninety patients developed symptomatic dysphagia within 3 years of onset, and 75 were evaluated for dysphagia severity using FEES. Survival from onset was shorter in patients with dysphagia within 3 years compared to those without (median: 4.2 years vs. 7.3 years; p < 0.001). Symptomatic dysphagia within 3 years of onset was an independent predictor of shorter survival in the multivariate Cox analysis. While the Hyodo score was higher in MSA-P than in MSA-C patients (p = 0.048), the Hyodo score was associated with survival in both MSA-C and MSA-P patients (log-rank p < 0.001 and p = 0.046, respectively). Conclusion: Symptomatic dysphagia within 3 years of onset predicts shorter survival in MSA-C and MSA-P patients. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies on multisystem atrophy (MSA) are scarce. Our aim has been to analyse 10-year incidence, point prevalence, survival, and the time to diagnosis of MSA in Navarre, a northern Spanish region. Methods: This is a population-based observational retrospective study, from 2012 to 2021, which covered the population of Navarre (followed until 31 December 2021). Data from various sources of health information were reviewed in order to identify all potential diagnoses of MSA, that were validated from medical records. Patients were included if they fulfilled the new Movement Disorder Society criteria. Results: We observed a crude average annual incidence rate (IR) of 0.49/100,000 person-years, with the highest occurring in the age group of 60–69 years. No significant IR differences by sex or subtype were observed. Point prevalence in December 2021 was 2.43/100,000 inhabitants. Joinpoint analysis for global incidence and prevalence experienced stable annual rates during the whole period, showing an upward trend for prevalence without a statistically significant slop. The median age at symptom onset was 65 years (range 47–76). The median time to diagnosis was 36 months, without statistically significant differences between sex, age at diagnosis or subtypes. Median time of survival from clinical onset was 7 years. Age of onset above 70 years and autonomic onset were associated with reduced survival. Conclusions: This is the first population-based epidemiological study on MSA in Spain. It provides detailed incidence and prevalence data for MSA that may be useful for appropriate management of health resources. [ABSTRACT FROM AUTHOR]

Purpose: This study identified the factors affecting cerebral microbleed (CMBs) development. Moreover, their effects on intelligence and memory and association with stroke in patients with germinoma who had long-term follow-up were evaluated. Methods: This study included 64 patients with germinoma who were histologically and clinically diagnosed with and treated for germinoma. These patients were evaluated cross-sectionally, with a focus on CMBs on susceptibility-weighted magnetic resonance imaging (SWI), brain atrophy assessed through volumetric analysis, and intelligence and memory. Results: The follow-up period was from 32 to 412 (median: 175.5) months. In total, 43 (67%) patients had 509 CMBs and 21 did not have CMBs. Moderate correlations were observed between the number of CMBs and time from initial treatments and recurrence was found to be a risk factor for CMB development. Increased temporal CMBs had a marginal effect on the processing speed and visual memory, whereas brain atrophy had a statistically significant effect on verbal, visual, and general memory and a marginal effect on processing speed. Before SWI acquisition and during the follow-up periods, eight strokes occurred in four patients. All of these patients had ≥ 15 CMBs on SWI before stroke onset. Meanwhile, 33 patients with < 14 CMBs or 21 patients without CMBs did not experience stroke. Conclusion: Patients with a longer time from treatment initiation had a higher number of CMBs, and recurrence was a significant risk factor for CMB development. Furthermore, brain atrophy had a stronger effect on memory than CMBs. Increased CMBs predict the stroke onset. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Gene editing technology repairs the conversion of the 6th base T to C in exon 7 of the paralogous SMN2 gene, compensating for the SMN protein expression and promoting the survival and function of motor neurons. However, low editing efficiency and unintended off‐target effects limit the application of this technology. Here, we optimized a TaC9‐adenine base editor (ABE) system by combining Cas9 nickase with the transcription activator‐like effector (TALE)‐adenosine deaminase fusion protein to effectively and precisely edit SMN2 without detectable Cas9 dependent off‐target effects in human cell lines. We also generated human SMA‐induced pluripotent stem cells (SMA‐iPSCs) through the mutation of the splice acceptor or deletion of the exon 7 of SMN1. TaC9‐R10 induced 45% SMN2 T6 > C conversion in the SMA‐iPSCs. The SMN2 T6 > C splice‐corrected SMA‐iPSCs were directionally differentiated into motor neurons, exhibiting SMN protein recovery and antiapoptosis ability. Therefore, the TaC9‐ABE system with dual guides from the combination of Cas9 with TALE could be a potential therapeutic strategy for SMA with high efficacy and safety. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed to investigate CT imaging features, pathological findings, and prognosis in patients with thyroid hemiatrophy (THA) associated with papillary thyroid carcinoma (PTC). Methods: This retrospective study included 225 patients with histopathologically proven PTC treated by surgical resection who underwent preoperative CT scanning. On CT images, THA was defined as thyroid parenchymal hemiatrophy on the ipsilateral side of PTC. CT findings, overall survival, and disease-free survival were compared between patients with and without THA. Pathological findings were also assessed in PTCs with and without THA. Results: THA was observed in 35 of 225 (16%) patients with PTC. Atrophic thyroid parenchyma was observed in the right lobe of 20 patients (57%) and in the left lobe of the remaining 15 patients (43%). With respect to the solid components within PTCs, contrast-enhanced CT attenuation (114.2 ± 18.2 vs. 126.7 ± 31.3 HU; p < 0.05) and CT attenuation change for contrast-enhanced CT minus unenhanced CT (60.2 ± 18.1 vs. 72.3 ± 31.0 HU; p < 0.05) were significantly lower in PTCs with THA than in those without THA. Histopathologically, almost all PTCs with THA (97%) had keloid-like collagen, which is broad bundles of hypocellular collagen with bright eosinophilic hyalinization, typically observed in keloid. However, no significant differences were observed in the prognosis between the two groups. Conclusion: THA was occasionally observed in patients with PTC. Weak contrast-enhancement was distinct characteristic of PTC patients with THA, which is probably caused by keloid-like collagen. [ABSTRACT FROM AUTHOR]

Objective: To evaluate efficacy of safflower polysaccharide in treatment of thymic atrophy induced by estradiol in mice. Methods: A total of 75 female ICR mice were divided into 5 groups: control group, model group, ubenimex group, SPS high dose group, SPS low dose group. Except for control group, each group was given intraperitoneal injection of estradiol benzoate every other day for 6 times. Treatment group began administration 24 h after the last parenteral administration, once a day for 10 days. Mice were sacrificed 24 hours after the last administration, and body weight, immune organ index, MDA and GST levels in plasma, peripheral blood cells and T cells changes were observed, thymus tissue was stained by HE staining and TUNEL cell apoptosis staining, and thymus output capacity was detected. Results: Both high and low doses of safflower polysaccharide significantly improved thymus index (P<0.05) in mice, increased leukocytes level in peripheral blood (P<0.05), proportions of CD3+CD4+T, CD3+CD8+T cells (P<0.05) and CD4+T/CD8+T, improved thymus tissue damage. High dose of safflower polysaccharide could significantly reduce apoptosis in thymus tissue and enhance thymus output. Conclusion: Safflower polysaccharide has a certain therapeutic effect on estradiol-induced thymus atrophy in mice. [ABSTRACT FROM AUTHOR]

Motorised arm supports for individuals with severe arm muscle weakness require precise compensation for arm weight and elevated passive joint impedance (e.g., joint stiffness as a result of muscle atrophy and fibrosis). Estimating these parameters in vivo, along with the arm's centre of mass, is challenging, and human evaluations of assistance can be subjective. To address this, a dummy arm was designed to replicate the human arm's anthropometrics, degrees of freedom, adjustable segment masses, and passive elbow joint impedance (eJimp). This study presents the design, anthropometrics, and verification of the dummy arm. It successfully mimics the human arm's range of motion, mass, and centre of mass. The dummy arm also demonstrates the ability to replicate various eJimp torque-angle profiles. Additionally, it allows for the tuning of the segment masses, centres of mass, and eJimp to match a representative desired target population. This simple, cost-effective tool has proven valuable for the development and verification of the Duchenne ARm ORthosis (DAROR), a motorised arm support, or 'exoskeleton'. This study includes recommendations for practical applications and provides insights into optimising design specifications based on the final design. It supplements the CAD design, enhancing the dummy arm's application for future arm-assistive devices. [ABSTRACT FROM AUTHOR]

Introduction: In the arms of patients with Amyotrophic lateral sclerosis (ALS) two peculiar patterns of dissociated muscular atrophy have been described: the split-hand sign (with predominant atrophy of the lateral aspect of the hand, compared to hypothenar eminence) and the split-hand-plus sign (SHPS), a predominant abductor pollicis brevis (ABP) atrophy with sparing of flexor pollicis longus (FPL). Aims: In this case–control study, we evaluated the diagnostic utility of a neurophysiological indicator of SHPS and assessed its association with clinical features. Methods: We prospectively studied 59 incident ALS patients, 61 patients with ALS-mimic disorders (OND) and 61 non-neurological controls (NNCs). ABP and FPL compound muscle action potentials (CMAP) amplitudes were obtained by supramaximal stimulation of median nerve at elbow. Split-hand plus index (SHPI) was calculated according to the formula: APB-CMAP/FPL-CMAP. Results: SHPI was significantly lower in ALS compared to OND patients and NNCs (p < 0.0001). SHPI value < 1 was observed in 2% of NNCs and 9% of OND patients and demonstrated an accuracy of 71% in differentiating ALS from OND and an accuracy of 74% in differentiating ALS from NNC. SHPI was associated with higher LMN score, and higher disease severity as quantified by the ALSFRS-r. Conclusion: Our results indicate that SHPI is a reliable indicator to distinguish ALS patients from ONDs and NNCs. SHPI was significantly associated to the degree of lower motor neuron impairment but showed no association with upper motoneuron impairment. [ABSTRACT FROM AUTHOR]

We examined how resistance exercise (RE), cycling exercise and disuse atrophy affect myosin heavy chain (MyHC) protein fragmentation. The 1boutRE study involved younger men (n = 8; 5 ± 2 years of RE experience) performing a lower body RE bout with vastus lateralis (VL) biopsies being obtained prior to and acutely following exercise. With the 10weekRT study, VL biopsies were obtained in 36 younger adults before and 24 h after their first/naïve RE bout. Participants also engaged in 10 weeks of resistance training and donated VL biopsies before and 24 h after their last RE bout. VL biopsies were also examined in an acute cycling study (n = 7) and a study involving 2 weeks of leg immobilization (n = 20). In the 1boutRE study, fragmentation of all MyHC isoforms (MyHCTotal) increased 3 h post‐RE (∼200%, P = 0.018) and returned to pre‐exercise levels by 6 h post‐RE. Interestingly, a greater magnitude increase in MyHC type IIa versus I isoform fragmentation occurred 3 h post‐RE (8.6 ± 6.3‐fold vs. 2.1 ± 0.7‐fold, P = 0.018). In 10weekRT participants, the first/naïve and last RE bouts increased MyHCTotal fragmentation 24 h post‐RE (+65% and +36%, P < 0.001); however, the last RE bout response was attenuated compared to the first bout (P = 0.045). Although cycling exercise did not alter MyHCTotal fragmentation, ∼8% VL atrophy with 2 weeks of leg immobilization increased MyHCTotal fragmentation (∼108%, P < 0.001). Mechanistic C2C12 myotube experiments indicated that MyHCTotal fragmentation is likely due to calpain proteases. In summary, RE and disuse atrophy increase MyHC protein fragmentation. Research into how ageing and disease‐associated muscle atrophy affect these outcomes is needed. Highlights: What is the central question of this study?How different exercise stressors and disuse affect skeletal muscle myosin heavy chain fragmentation.What is the main finding and its importance?This investigation is the first to demonstrate that resistance exercise and disuse atrophy lead to skeletal muscle myosin heavy chain protein fragmentation in humans. Mechanistic in vitro experiments provide additional evidence that MyHC fragmentation occurs through calpain proteases. [ABSTRACT FROM AUTHOR]

The gradual deterioration of physiological systems with ageing makes it difficult to maintain skeletal muscle mass (sarcopenia), at least partly due to the presence of 'anabolic resistance', resulting in muscle loss. Sarcopenia can be transiently but markedly accelerated through periods of muscle disuse‐induced (i.e., unloading) atrophy due to reduced physical activity, sickness, immobilisation or hospitalisation. Periods of disuse are detrimental to older adults' overall quality of life and substantially increase their risk of falls, physical and social dependence, and early mortality. Disuse events induce skeletal muscle atrophy through various mechanisms, including anabolic resistance, inflammation, disturbed proteostasis and mitochondrial dysfunction, all of which tip the scales in favour of a negative net protein balance and subsequent muscle loss. Concerningly, recovery from disuse atrophy is more difficult for older adults than their younger counterparts. Resistance training (RT) is a potent anabolic stimulus that can robustly stimulate muscle protein synthesis and mitigate muscle losses in older adults when implemented before, during and following unloading. RT may take the form of traditional weightlifting‐focused RT, bodyweight training and lower‐ and higher‐load RT. When combined with sufficient dietary protein, RT can accelerate older adults' recovery from a disuse event, mitigate frailty and improve mobility; however, few older adults regularly participate in RT. A feasible and practical approach to improving the accessibility and acceptability of RT is through the use of resistance bands. Moving forward, RT must be prescribed to older adults to mitigate the negative consequences of disuse atrophy. What is the topic of this review?Use of resistance exercise training to prevent or mitigate the disuse‐induced muscle atrophy in an ageing population.What advances does it highlight?The review highlights several potential mechanisms of disuse‐induced muscle atrophy and strategies before, during and following disuse to prevent, mitigate and recover lost muscle. [ABSTRACT FROM AUTHOR]

Background: When kidney function is consistently impaired, as in the case of chronic kidney disease (CKD) or chronic renal failure (CRF) or, diagnostic criteria include an unusually high blood creatinine level for longer than 3 months or the glomerular filtration rate (GFR) to be below 60 ml/min / 1.73 m2. Loss of energy stores and body proteins is one indicator of a worsening nutritional condition in patients with poorly controlled chronic renal disease, especially in its latter stages. Cases who had end-stage kidney disease (ESKD) are already fragile due to muscular atrophy, sarcopenia, and cachexia; furthermore, malnutrition is a powerful predictor of illness and death in this population. We intended to provide an outline of hematological parameters that could reflect inflammatory and nutritional state in dialysis patient. Conclusion:Cytokines like interleukin-6 (IL-6), interleukin-1 (IL-1), or tumor necrosis factor (TNF), gastric mediators like ghrelin as well as leptin, and adipokines may all play a role in mediating the anorexic process. More research into the identification and prevention of malnutrition, in particular, is necessary due to the complicated interaction between inflammatory and nutritional parameters during chronic kidney disease (CKD). We require additional studies on these mediators. [ABSTRACT FROM AUTHOR]

This study evaluated changes over time in skeletal muscle atrophy, expressions of skeletal muscle anabolic and catabolic genes, and mitochondrial activity by skeletal muscle type in an adenine-induced chronic kidney disease (CKD) model. A CKD model was successfully established by feeding male Wistar rats a 0.75% adenine diet for 4 weeks starting at 8 weeks of age. Control and CKD groups were sacrificed at 12 and 20 weeks of age. The back muscles were analyzed histologically, and succinate dehydrogenase (SDH) staining was performed to evaluate mitochondrial activity. Gene expressions of myogenic determination gene number 1 and myogenin as indicators of muscle anabolism, atrogin-1 and muscle RING-finger protein-1 (MuRF1) as indicators of muscle catabolism, and peroxisome proliferator-activated receptor-γ coactivator-1-α as a marker of mitochondrial biogenesis were assessed. Type I and type II muscle cross-sectional areas (CSAs) were decreased at 12 weeks, but type I muscle CSA was recovered at 20 weeks. SDH staining was lower in CKD than in control rats at 12 weeks, but no significant difference was observed at 20 weeks. Increased expressions of myogenin, atrogin-1, and MuRF-1 were observed only at 12 weeks, but no differences were observed at 20 weeks. The adenine-induced CKD rat model appears to show changes in muscle atrophy over time. [ABSTRACT FROM AUTHOR]

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), that starts with atrophic lesions in the outer retina that expand to cover the macula and fovea, leading to severe vision loss over time. Pigment Epithelium-Derived Factor (PEDF) has a diverse-range of properties, including its ability to promote cell survival, reduce inflammation, inhibit angiogenesis, combat oxidative stress, regulate autophagy, and stimulate anti-apoptotic pathways, making it a promising therapeutic candidate for GA. However, the relatively short half-life of PEDF protein has precluded its potential as a clinical therapy for GA since it would require frequent injections. Therefore, we describe administration of a PEDF gene, comparing and contrasting delivery routes, viral and nonviral vectors, and consider the critical challenges for PEDF as a neuroprotectant for GA. [ABSTRACT FROM AUTHOR]

This article discusses a case of anti-Melanoma Differentiation-Associated Gene 5 (anti-MDA5) dermatomyositis, a rare form of immune-mediated dermatomyositis. The patient, a 73-year-old male, presented with muscle weakness and falls but did not exhibit the typical cutaneous findings or rapidly progressive lung disease associated with anti-MDA5 dermatomyositis. The article highlights the diverse phenotypic spectrum and prognosis of the disease, emphasizing the need for clinicians to consider the diagnosis even in the absence of classic symptoms. The patient's course was complicated by acute colonic pseudo-obstruction, a rare complication of autoimmune diseases. Despite the atypical presentation, the patient showed improvement with treatment and remained stable at follow-up. [Extracted from the article]

Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1. [ABSTRACT FROM AUTHOR]

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Inhalant misuse and inhalant use disorder are global public health concern that impacts adolescents but can occur throughout life. Toluene is the most commonly misused inhalant. Toluene use leads to significant neuroanatomic, cognitive, and psychiatric deficits. The purpose of this study was to review and summarize the effects of toluene and present a case of a middle-aged patient with an inhalant use disorder. A literature review was conducted to evaluate imaging, neurocognitive, and psychiatric consequences of toluene misuse. The common imaging findings amongst those who misuse toluene were cerebral and cerebellar atrophy, ventricular dilation, loss of gray-white matter differentiation, corpus callosum thinning, and diffuse white matter changes. Concerning cognition, toluene misusers were shown to have deficits in intelligence, attention, memory, visuospatial function, and complex cognition. In addition, toluene users also commonly presented with apathy, flat affect, hallucinations, delusions, anxiety, depression, and insomnia. The neuroanatomical, neurocognitive, and psychiatric effects of toluene misuse are profound. These deficits can make inhalant use disorder difficult to treat. Therefore, evidence-based treatments that recognize and address these domain-specific neurocognitive deficits are needed. [ABSTRACT FROM AUTHOR]

Introduction: Atypical parkinsonisms (APs) present various symptoms including motor impairment, cognitive decline, and autonomic dysfunction. Olfactory loss (OL), being a significant non-motor symptom, has emerged as an under-evaluated, yet potentially valuable, feature that might aid in the differential diagnosis of APs. State of the art: The most pronounced OL is usually associated with Dementia with Lewy Bodies (DLB). While the view about the normosmic course of Multiple System Atrophy (MSA) remains unchanged, research indicates that mild OL may occur in a subset of patients with Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). This might be linked to the deposition of abnormal protein aggregates in the central nervous system. Clinical significance: The aim of this review is to discuss the role of OL and its degree and pattern in the pathogenesis and course of APs. Olfactory testing could serve as a non-invasive, quick screening tool to differentiate between APs and project disease progression. Future directions: There is a need for further evaluation of this topic. This may lead to the development of standardized olfactory testing protocols that could be implemented in clinical practice, making differential diagnosis of APs more convenient. Understanding differences in the sense of smell could create an avenue for more targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Inherited pediatric motor neuron diseases (MNDs) are a group of neurodegenerative disorders characterized by the degeneration of motor neurons in the brain and the spinal cord. These diseases can manifest as early as infancy and originate from inherited pathogenic mutations in known genes. Key clinical features of MNDs include muscle weakness, hypotonia, and atrophy due to the degeneration of lower motor neurons or spasticity, hypertonia, and hyperreflexia caused by upper motor neuron dysfunction. The course of the disease varies among individuals and is influenced by the specific subtype. Methods: We performed a non-systematic, narrative clinical review, employing a systematic methodology for the literature search and article selection to delineate the features of hereditary pediatric motor neuron diseases. Results: The growing availability of advanced molecular testing, such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), has expanded the range of identified genetic factors. These advancements provide insights into the genetic complexity and underlying mechanisms of these disorders. As more MND-related genes are discovered, the accumulating genetic data will help prioritize promising candidate genes for future research. In some cases, targeted treatments based on specific genetic mechanisms have already emerged, underscoring the critical role of early and timely diagnosis in improving patient outcomes. Common MNDs include amyotrophic lateral sclerosis, spinal muscular atrophy, and bulbar spinal muscular atrophy. Conclusion: This narrative clinical review covers the clinical presentation, genetics, molecular features, and pathophysiology of inherited pediatric MNDs. [ABSTRACT FROM AUTHOR]

Purpose: Assistive technologies based on IoT can contribute to improve quality of living of patients with severe motor difficulties by providing partial or total independence. The aim of this work was to analyse the usability and performance of an assistive system based on the IoT when is evaluated by a child patient with spinal muscular atrophy type 1 (SMA-I). Materials and methods: The study involved a child with SMA-I and his caregiver. The materials used include an M5Stack Core2 kit, a mobile app, and a smart switch based on the ESP-01S card. The patient sends requests to the caregiver from the app installed on the M5Stack Core2 to a mobile app, and controls smart switches located in the rooms. The system was tested by the participants for a period of 30 days to later evaluate its usability and performance. Results: The results show that the control function of smart switches is the most used and there is no decrease in interactions over the days for the system in general. In addition, the scores obtained from both usability tests (patient and caregiver) were 87.5% and 90%, respectively. The average performance of the entire system was 93.33%. Conclusion: The application of assistive technologies based on the IoT allows obtaining a practical solution that improves the development of daily activities in a patient with SMA-I. Implications for Rehabilitation: A low-cost device can contribute to improve the quality of living of spinal muscular atrophy patients by favouring partial or total independence. IoT-based assistive technologies allow obtaining practical solutions that improve the development of daily activities. [ABSTRACT FROM AUTHOR]

Purpose: There are few options for treatment of dysphonia secondary to vocal pathology related to lamina propria scar, atrophy, sulcus, or inflammatory disorders. Platelet rich plasma (PRP) may provide anti-inflammatory and regenerative properties seen with other tissue engineering therapies without the risks associated with these treatments. We evaluated vocal fold (VF) injection of PRP for feasibility, phonatory effects, patient satisfaction and durability. Methods: Patients with dysphonia secondary to vocal fold scar, atrophy, sulcus and inflammatory lesions were included. PRP injections were administered in office, to bilateral vocal folds. Patients were followed up at 1 week, 1 month, 3 months and 6 months to assess outcomes (GRBAS scale, maximum phonation time, vocal fatigue index (VFI), voice handicap index (VHI-10) and stroboscopy). Results: 75 intracordal PRP injections were administered to 48 patients. All injections were completed, and no adverse reactions were experienced. Improvements in VHI-10 scores at 1,3,6 months were seen (mean VHI 21.73 at baseline, 15.62 at six months, p < 0.001). 72.3% rated improvement at 7 or above on Likert scale. 95.7% of patients would consider a future PRP injection. Secondary outcomes VFI, MPT, and GRBAS also demonstrated significant improvements over time. Patients receiving a single PRP injection (n = 26) still demonstrated significant VHI-10 improvements at 1,3 and 6 months. Conclusions: VF office PRP injections are feasible and safe and can provide phonatory benefit and reduce vocal effort in benign VF disorders. A single PRP injection is sufficient to provide sustained benefit in some cases. Level of evidence: Level III: prospective cohort study. [ABSTRACT FROM AUTHOR]

Purpose: Identifying outcome measurements instruments (OMIs) to evaluate treatment efficacy in patients with vocal fold atrophy and/or sulcus. Methods: Systematic review of records published before March 2021 by searching Pubmed and EMBASE. Included studies reported on adults (> 18 year) with dysphonia caused by glottic insufficiency due to vocal fold atrophy with or without sulcus, who were enrolled into a randomized controlled trial, a non-randomized controlled trial, a case-controlled study or a cohort study. All included studies described an intervention with at least one outcome measurement. Results: A total of 5456 studies were identified. After removing duplicates, screening title and abstract and full text screening of selected records, 34 publications were included in final analysis. From these 50 separate OMIs were recorded and categorized according to the ELS protocol by DeJonckere et al. (Eur Arch Otorhinolaryngol 258: 77–82, 2001). With most OMIs being used in multiple studies the total number of OMIs reported was 265. Nineteen (19) individual OMIs accounted for 80% of reports. The most frequently used OMIs according to category were: VHI and VHI-10 (subjective evaluation); G of GRBAS (perceptual evaluation); F0, Jitter and Shimmer (acoustic evaluation); MPT and MFR (aerodynamic evaluation) and glottic closure and mucosal wave (endoscopic evaluation). Of these OMIs VHI had a high percentage of significance of 90%. Conclusion: This systematic review identifies the most used OMIs in patients with glottic incompetency due to vocal fold atrophy and/or sulcus as a step toward defining a Core Outcome Set (COS) for this population. PROSPERO registration: 238274. [ABSTRACT FROM AUTHOR]

Doxorubicin‐based chemotherapy is a widely used first‐line treatment for breast cancer, yet it is associated with various side effects, including splenic atrophy. However, the pathogenic mechanisms underlying doxorubicin‐induced atrophy of the spleen remain unclear. This study investigates that doxorubicin treatment leads to splenic atrophy through several interconnected pathways involving histological changes, an inflammatory response, and apoptosis. Immunohistochemical and western blot analyses revealed reduced size of white and red pulp, decreased cellularity, amyloidosis, and fibrotic remodeling in the spleen following doxorubicin treatment. Additionally, increased secretion of pro‐inflammatory cytokines was detected using an antibody array and enzyme‐linked immunosorbent assay (ELISA), which triggers inflammation through the regulation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor‐kappa B (NF‐κB) signaling pathways. Further analysis revealed that the loss of regulators and effectors of the oxidative defense system, including sirtuin (Sirt)3, Sirt5, superoxide dismutase (SOD)1, and SOD2, was implicated in the upstream regulation of caspase‐dependent cellular apoptosis. These findings provide insights on the pathogenic mechanisms underlying doxorubicin‐induced splenic atrophy and suggest that further investigation may be warranted to explore strategies for managing potential side effects in breast cancer patients treated with doxorubicin. Doxorubicin, a common breast cancer treatment, induces splenic atrophy through interconnected pathways. This study reveals that doxorubicin causes white and red pulp shrinkage, cellular depletion, and fibrosis. Elevated pro‐inflammatory cytokines trigger inflammation via STAT3 and NF‐κB pathways. Downregulation of oxidative defense regulators (Sirt3, Sirt5, SOD1, and SOD2) contributes to caspase‐dependent apoptosis. These findings elucidate the mechanisms of doxorubicin‐induced splenic atrophy, highlighting the need for strategies to mitigate side effects in breast cancer patients. [ABSTRACT FROM AUTHOR]

The influence of brain atrophy on sleep microstructure in Spinocerebellar Ataxias (SCAs) has not been extensively explored limiting the use of these sleep traits as surrogate biomarkers of neurodegeneration and clinical phenotype. The objective of the study is to explore the relationship between sleep microstructure and brain atrophy in SCA2 and its role in the clinical phenotype. Fourteen SCA2 mutation carriers (7 pre-manifest and 7 manifest subjects) underwent polysomnographic, structural MRI, and clinical assessments. Particularly, markers of REM and non-REM sleep microstructure, measures of cerebellar and brainstem atrophy, and clinical scores were analyzed through correlation and mediation analyses. The sleep spindle activity exhibited a negative correlation with the number of trials required to complete the verbal memory test (VMT), and a positive correlation with the cerebellar volume, but the significance of the latter correlation did not survive multiple testing corrections. However, the causal mediation analyses unveiled that sleep spindle activity significantly mediates the association between cerebellar atrophy and VMT performance. Regarding REM sleep, both phasic EMG activity and REM sleep without atonia exhibited significant associations with pontine atrophy and disease severity measures. However, they did not demonstrate a causal mediation effect between the atrophy measures and disease severity. Our study provides evidence about the association of the pontocerebellar atrophy with sleep microstructure in SCA2 offering insights into the cerebellar involvement in cognition via the control of the sleep spindle activity. Therefore, our findings may help to understand the disease pathogenesis and to better characterize sleep microstructure parameters as disease biomarkers. Clinical trial registration number (TRN): No applicable. [ABSTRACT FROM AUTHOR]

Background and Objective: The Food and Drug Administration recently approved treatments of geographic atrophy (GA). Our study aims to quantify the time for a lesion to reach the central fovea based on reduction of GA growth rates from therapeutics compared to the natural history. Patients and Methods: A previously published study calculates local border expansion rate of GA lesions at varying retinal eccentricities. In this study, we use these rates to model GA expansion toward the fovea and the effects of treatments that reduce growth in GA area by 15% to 45% on lesions of varying sizes with posterior margin 250, 500, 750, 1000, 1250, 1500, and 3000 µm from the fovea. Results: Lesions with an area 8 mm2 and posterior edge 500 µm from the fovea will reach the fovea in 5.08 years with no treatment, but the same lesions will reach the fovea in 5.85, 6.52, 7.36, and 8.46 years with a treatment that reduces growth in GA area by 15%, 25%, 35%, and 45%, respectively. Conclusions: Distance of the posterior edge of the lesion was the primary factor in GA growth toward the fovea, and lesion size only minimally affects growth rates of GA. Based on the efficacy of current and future therapeutics and distance of GA to the fovea, our study provides the marginal time benefit of treatment to guide patients and clinicians, placing both the natural history of GA and the effects of current and future treatments into clinical context. [Ophthalmic Surg Lasers Imaging Retina 2024;55:576–585.] [ABSTRACT FROM AUTHOR]

A 17-year-old boy presented with a full-thickness macular hole, with 20/20 vision with eccentric fixation in the left eye. Examination of the left eye showed a large macular hole with a base diameter measuring 1,680 μm and temporal macular and mid-peripheral retinal atrophy on ultra-high-definition optical coherence tomography (OCT) scans. Microperimetry showed eccentric fixation with good nasal sensitivity. A 12 x 12-mm extended-field swept-source OCT angiogram showed flow loss in the temporal macula, with slight reduction noted in the choriocapillaris. Given excellent visual acuity, good tolerance by the patient, and large atrophic hole, the decision was made for observation rather than surgery. [Ophthalmic Surg Lasers Imaging Retina 2024;55:607–612.] [ABSTRACT FROM AUTHOR]

We have described the hyperreflective ganglion cell layer band (HGCB) in a series of cases of gyrate atrophy. Clinical fundus examination and multimodal imaging which included optical coherence tomography (OCT) was done in all cases. Four patients (one male, three female) were studied. In all four cases, a hyperreflective band was noted in the ganglion cell layer. In three patients, the band was continuous, and in one patient, the band was patchy. To conclude, HGCB is a novel OCT sign in gyrate atrophy and can be valuable in prognostication of disease. [Ophthalmic Surg Lasers Imaging Retina 2024;55:598–602.] [ABSTRACT FROM AUTHOR]

Aims: Spinal muscular atrophy (SMA) is a life‐limiting paediatric motor neuron disease characterised by lower motor neuron loss, skeletal muscle atrophy and respiratory failure, if untreated. Revolutionary treatments now extend patient survival. However, a limited understanding of the foundational neuropathology challenges the evaluation of therapeutic success. As opportunities to study treatment‐naïve tissue decrease, we have characterised spinal cord pathology in severe infantile SMA using gold‐standard techniques, providing a baseline to measure treatment success and therapeutic limitations. Methods: Detailed histological analysis, stereology and transmission electron microscopy were applied to post‐mortem spinal cord from severe infantile SMA patients to estimate neuron number at the end of life; characterise the morphology of ventral horn, lateral horn and Clarke's column neuron populations; assess cross‐sectional spinal cord area; and observe myelinated white matter tracts in the clinically relevant thoracic spinal cord. Results: Ventral horn neuron loss was substantial in all patients, even the youngest cases. The remaining ventral horn neurons were small with abnormal, occasionally chromatolytic morphology, indicating cellular damage. In addition to ventral horn pathology, Clarke's column sensory–associated neurons displayed morphological features of cellular injury, in contrast to the preserved sympathetic lateral horn neurons. Cellular changes were associated with aberrant development of grey and white matter structures that affected the overall dimensions of the spinal cord. Conclusions: We provide robust quantification of the neuronal deficit found at the end of life in SMA spinal cord. We question long‐accepted dogmas of SMA pathogenesis and shed new light on SMA neuropathology out with the ventral horn, which must be considered in future therapeutic design. [ABSTRACT FROM AUTHOR]

Aims: Although the neuroanatomical distribution of tau and amyloid‐β is well studied in Alzheimer's disease (AD) (non)‐amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid‐β and phosphorylated tau in a clinically well‐defined prospectively collected AD cohort. Methods: Clinical variants were diagnosed antemortem, and brain tissue was collected post‐mortem. Typical AD (n = 10), behavioural/dysexecutive AD (n = 6), posterior cortical atrophy (PCA) AD (n = 3), and controls (n = 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid‐β, CD68, MHC‐II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology. Results: Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid‐β was neocortical‐dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE‐NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC‐II were hippocampal‐dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC‐II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants. Conclusions: Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation‐based biomarkers and future therapeutics. [ABSTRACT FROM AUTHOR]

Objective: To clarify the effect of growth and advancing age on lymphatic capillarization in rat skeletal muscles, we examined the histological and biochemical changes of lymphatic capillaries in different fiber types of skeletal muscles across juvenile, young, and middle‐aged generations. Methods: We collected the tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) muscles. Immunohistochemical staining using LYVE‐1 and CD31 markers was used for lymphatic and blood capillaries, respectively. Real‐time PCR was used to analyze mRNA expression of lymphangiogenic factors. Results: The density of LYVE‐1‐positive lymphatic capillaries in the muscles peaked during the juvenile period and subsequently decreased with increasing age. In contrast to blood capillaries, fast‐twitch dominant muscles (i.e., TA and EDL) exhibited an age‐related decrease in lymphatic capillaries. Similar to blood capillaries, lymphatic capillaries were abundant in SOL, a slow‐twitch dominant muscle, which showed less susceptibility to age‐related lymphatic decline. The mRNA expression of lymphangiogenic factors was significantly upregulated in SOL and decreased in all muscles of middle‐aged rats. Conclusions: The age‐related decrease of lymphatic capillaries in fast‐twitch muscles might be associated with age‐related muscle atrophy. [ABSTRACT FROM AUTHOR]

Background: Recent magnetic resonance imaging (MRI) studies have established that brain iron accumulation might accelerate cognitive decline in Alzheimer's disease (AD) patients. Both normal aging and AD are associated with cerebral atrophy in specific regions. However, no studies have investigated aging- and AD-selective iron deposition-related cognitive changes during normal aging. Here, we applied quantitative susceptibility mapping (QSM) to detect iron levels in cortical signature regions and assessed the relationships among iron, atrophy, and cognitive changes in older adults. Methods: In this Taizhou Imaging Study, 770 older adults (mean age 62.0 ± 4.93 years, 57.5% women) underwent brain MRI to measure brain iron and atrophy, of whom 219 underwent neuropsychological tests nearly every 12 months for up to a mean follow-up of 2.68 years. Global cognition was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Domain-specific cognitive scores were obtained from MoCA subscore components. Regional analyses were performed for cortical regions and 2 signature regions where atrophy affected by aging and AD only: Aging (AG) -specific and AD signature meta-ROIs. The QSM and cortical morphometry means of the above ROIs were also computed. Results: Significant associations were found between QSM levels and cognitive scores. In particular, after adjusting for cortical thickness of regions of interest (ROIs), participants in the upper tertile of the cortical and AG-specific signature QSM exhibited worse ZMMSE than did those in the lower tertile [ β = -0.104, p = 0.026; β = -0.118, p = 0.021, respectively]. Longitudinal analysis suggested that QSM values in all ROIs might predict decline in ZMoCA and key domains such as attention and visuospatial function (all p < 0.05). Furthermore, iron levels were negatively correlated with classic MRI markers of cortical atrophy (cortical thickness, gray matter volume, and local gyrification index) in total, AG-specific signature and AD signature regions (all p < 0.05). Conclusion: AG- and AD-selective iron deposition was associated with atrophy and cognitive decline in elderly people, highlighting its potential as a neuroimaging marker for cognitive aging. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA), identified over a century ago, is characterized by severe muscle wasting and early mortality. Despite its rarity, the high carrier frequency of the responsible genetic mutations and the variability in its manifestations make it a significant research focus. This prospective cross-sectional descriptive study evaluated health-related quality of life (HRQoL) across eight health domains in 43 Romanian SMA patients treated with nusinersen, using the SF-36 questionnaire to analyze influencing factors. The survey was conducted online with informed consent, and the data were analyzed using MedCalc software, employing both parametric and non-parametric statistical tests for accurate interpretation. The results revealed significant variations in HRQoL. Most patients were non-ambulatory (74.4%), reflecting SMA's impact on mobility. Urban residents reported better outcomes, particularly in physical functioning (p = 0.014), which may be attributed to improved access to healthcare services. Younger participants (under 14), represented by proxy responses, noted better general health (p = 0.0072) and emotional well-being (p = 0.0217) compared to older participants. These findings suggest that younger patients or their proxies perceive a better health status, highlighting the need for age-specific approaches in SMA management and the potential optimistic bias associated with proxy reporting on perceived health outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the influence of submacular hemorrhage (SMH) at baseline on long-term visual outcomes of patients with typical age-related macular degeneration (tAMD) and polypoidal choroidal vasculopathy (PCV) treated with intravitreal aflibercept (IVA). Methods: In this retrospective study, eyes of treatment-naïve patients with tAMD and PCV who initiated IVA under a treat-and-extend regimen and were followed up for ≥ 5 years were classified into the tAMD-SMH (+), tAMD-SMH (-), PCV-SMH (+), and PCV-SMH (-) groups based on the presence of SMH at baseline. Best-corrected visual acuity (BCVA) changes and macular fibrosis and atrophy incidences were assessed. Results: This study included 127 eyes (127 patients), including 51 with tAMD and 76 with PCV; 18 eyes had SMH at baseline. In the tAMD-SMH (+) group (n = 6), the mean logMAR BCVA significantly deteriorated from 0.59 ± 0.45 at baseline to 0.88 ± 0.47 at the final visit (P = 0.024). No significant BCVA changes were observed in the tAMD-SMH (-) (n = 45), PCV-SMH (+) (n = 12), or PCV-SMH (-) (n = 64) groups (all P > 0.05). The tAMD-SMH (+) group showed a significantly higher incidence of macular fibrosis at the final visit than did the tAMD-SMH (-) group (P = 0.042). There was no influence of baseline SMH on the macular fibrosis incidence in eyes with PCV and the macular atrophy incidence in eyes with tAMD and PCV. Conclusion: The presence of SMH at baseline resulted in poorer long-term visual acuity in eyes with tAMD, even with aflibercept treatment. However, no such influence was observed in eyes with PCV. [ABSTRACT FROM AUTHOR]

Background: Menopause, a natural phase in a woman's life, often adversely affects physical, mental, sexual, and emotional well-being due to low estrogen levels. This study examines the impact of vaginal ovules with tocopherol acetate (Filme Gyno-V® ovules, manufactured by Panin Srl and distributed by Hulka Srl, Italy), 500 mg per ovule, on vaginal health in pre- and menopausal women. Methods: Fifty women aged 50–70 were divided into menopausal (28) and premenopausal (22) cohorts and treated with the ovules for two weeks, with assessments before and after treatment. Results: The findings showed that distressing symptoms of vaginal atrophy, such as dryness, itching, and pain during intercourse, were resolved post-treatment. A molecular analysis revealed a reduction in Escherichia coli in both cohorts and an increase in three species of Lactobacillus in premenopausal patients. Conclusions: This study concludes that Filme Gyno-V ovules may benefit vaginal health by alleviating atrophy symptoms and promoting healthy vaginal microbiota. [ABSTRACT FROM AUTHOR]

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Introduction: Advanced age-related macular degeneration (AMD) is a major cause of vision loss. Therefore, there is interest in precursor lesions that may predict or prevent the onset of advanced AMD. One such lesion is a shallow separation of the retinal pigment epithelium (RPE) and Bruch's membrane (BM), which is described by various terms, including double-layer sign (DLS). Methods: In this article, we aim to examine and clarify the different terms referring to shallow separation of the RPE and BM. We also review current evidence on the outcomes associated with DLS: firstly, whether DLS is predictive of exudative neovascular AMD; and secondly, whether DLS has potential protective properties against geographic atrophy. Results: The range of terms used to describe a shallow separation of the RPE and BM reflects that DLS can present with different characteristics. While vascularised DLS appears to protect against atrophy but can progress to exudation, non-vascularised DLS is associated with an increased risk of atrophy. Optical coherence tomography (OCT) angiography (OCTA) is the principal method for identifying and differentiating various forms of DLS. If OCTA is unavailable or not practically possible, simplified classification of DLS as thick or thin, using OCT, enables the likelihood of vascularisation to be approximated. Research is ongoing to automate DLS detection by applying deep-learning algorithms to OCT scans. Conclusions: The term DLS remains applicable for describing shallow separation of the RPE and BM. Detection and classification of this feature provides valuable information regarding the risk of progression to advanced AMD. However, the appearance of DLS and its value in predicting AMD progression can vary between patients. With further research, individualised risks can be confirmed to inform appropriate treatment. Plain Language Summary: Age-related macular degeneration (AMD) is an eye disease that may develop in older people, usually those aged over 60 years. Early in the disease, people often do not show any symptoms, but as the disease progresses, vision loss may occur. The advanced forms of AMD are called neovascular AMD (also called "wet" AMD) and advanced dry AMD (called geographic atrophy; GA). It is important to identify features and signs on eye scans that can help to predict if someone with AMD will develop an advanced form of the disease because this will help doctors plan the most appropriate treatment. One such feature on eye scans is the double-layer sign (DLS). In this article, we summarise the different names used for DLS, and assess if having a DLS increases the likelihood of someone with early AMD developing wet AMD or GA. We conclude that how DLS looks varies between people, which leads to DLS being called by various names. Someone with early AMD and a DLS containing blood vessels may be more likely to develop wet AMD; whereas someone with early AMD and a DLS without blood vessels may be more likely to develop GA. Taking photos of the eye using optical coherence tomography angiography imaging is the main method of identifying DLS and confirming whether it contains blood vessels. [ABSTRACT FROM AUTHOR]

Introduction: Nusinersen clinical trials have limited data on adolescents and adults with 5q-associated spinal muscular atrophy (SMA). We conducted a systematic literature review (SLR) and meta-analysis to assess effectiveness of nusinersen in adolescents and adults with SMA in clinical practice. Methods: Our search included papers published 12/23/2016 through 07/01/2022 with ≥ 5 individuals ≥ 13 years of age and with ≥ 6 months' data on ≥ 1 selected motor function outcomes [Hammersmith Functional Motor Scale–Expanded (HFMSE), Revised Upper Limb Module (RULM), and Six-Minute Walk Test (6MWT)]. For meta-analysis, effect sizes were pooled using random-effects models. To understand treatment effects by disease severity, subgroup meta-analysis by SMA type and ambulatory status was conducted. Results: Fourteen publications including 539 patients followed up to 24 months met inclusion criteria for the SLR. Patients were age 13–72 years and most (99%) had SMA Type II or III. Modest improvement or stability in motor function was consistently observed at the group level. Significant mean increases from baseline were observed in HFMSE [2.3 points (95% CI 1.3–3.3)] with 32.1% (21.7–44.6) of patients demonstrating a clinically meaningful increase (≥ 3 points) at 18 months. Significant increases in RULM were consistently found, with a mean increase of 1.1 points (0.7–1.4) and 38.3% (30.3–47.1) showing a clinically meaningful improvement (≥ 2 points) at 14 months. Among ambulatory patients, there was a significant increase in mean 6MWT distance of 25.0 m (8.9–41.2) with 50.9% (33.4–68.2) demonstrating a clinically meaningful improvement (≥ 30 m) at 14 months. The increases in HFMSE were greater for less severely affected patients, whereas more severely affected patients showed greater improvement in RULM. Conclusions: Findings provide consolidated evidence that nusinersen is effective in improving or stabilizing motor function in many adolescents and adults with a broad spectrum of SMA. Plain Language Summary: Motor neurons are specialized cells in the brain and spinal cord that control the function of muscles. People with spinal muscular atrophy (SMA) do not make enough survival motor neuron (SMN) protein, which motor neurons need to function. As a result, people with SMA experience decreased muscle function that gets worse over time. Nusinersen is a drug that increases the amount of SMN protein made in the brain and spinal cord. However, most clinical trials of nusinersen have been in infants and children with SMA. Less is known about the effects of nusinersen in teenagers and adults with SMA who may have less severe but still progressive forms of the disease. In this manuscript, we first conducted a thorough review and analysis of research published by investigators who treated teenagers and adults with nusinersen for up to 24 months. We then used an additional analysis, called a meta-analysis, that allowed us to combine the information from several articles, so that we could better understand whether nusinersen helped these patients. We looked at 3 tests that investigators used to see how nusinersen affected patients' motor function. The Hammersmith Functional Motor Scale–Expanded (HFMSE) assesses upper and lower limb motor function; the Revised Upper Limb Module (RULM) evaluates upper limb function; and the Six-Minute Walk Test (6MWT) measures the maximum distance a person can walk in 6 minutes. Our study showed that nusinersen can improve motor function or prevent motor function from getting worse in many teenagers and adults with SMA. [ABSTRACT FROM AUTHOR]

Amibegron, a β3‐adrenergic receptor (B3AR) agonist, has recently been shown to provide therapeutic effects for chronic rotator cuff (RC) tears by inducing the expression of uncoupling protein 1 (UCP‐1), a marker of brown fat, in fibroadipogenic progenitors (FAPs). However, it remains to be seen if these beneficial effects hold true with age and in older, more clinically relevant populations. This study seeks to understand the impacts of aging on the efficacy of amibegron to treat chronic RC tears. Young (4‐month‐old) and aged (33‐month‐old) C57BL/6 mice underwent a RC injury procedure with delayed repair (DR). Mice were equally randomized to receive amibegron or dimethyl sulfoxide (DMSO) treatments after repair. Functional ability was measured at baseline and 6‐weeks after DR. Wet muscle weight and histology of injured and contralateral supraspinatus were also analyzed 6‐weeks post‐DR. For in vitro histology and real‐time quantitative PCR experiments, FAPs were isolated from young and aged mice via fluorescence‐activated cell sorting. Young and aged FAPs were treated with amibegron or DMSO either immediately after seeding (early exposure) or 8‐days after seeding (late exposure). In vitro results showed that amibegron‐mediated FAP UCP‐1 expression decreases with age. In vivo data demonstrated that aged mice have a decreased responsiveness to amibegron and decreased propensity for intramuscular FAP UCP‐1 expression. Further, delayed amibegron treatment with RC repair did not lead to improvements in muscle atrophy and functional outcomes. Our findings demonstrate that age and the timing of interventions play a critical role in FAP‐targeted therapeutics for chronic injuries. [ABSTRACT FROM AUTHOR]

The lack of effective treatments for alleviating irreversible skeletal muscle atrophy caused by peripheral nerve dysfunction is a clinical problem. To identify therapeutic targets, signaling pathways in muscle cells activated by denervation have been explored, including the important roles of Cx43, a kind of protein that forms gap junctions, in other types of pathological process. The present study investigated the negative role of Cx43 in aggravated muscle cell degeneration following denervation. The blueberry extract was applied orally on mice models, and its protective effect against denervated skeletal muscle atrophy was found by wet weight measurement and tissue staining observation. Cx43/Akt pathway in denervated muscle cells was modulated by blueberry extract. In conclusion, the negative effects of Cx43 on denervated skeletal muscle atrophy were attenuated by blueberry extract by regulating the Akt pathway. [ABSTRACT FROM AUTHOR]

In response to peroxynitrite (ONOO−) generation, myogenic stem satellite cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198 and Y250) predominantly on fast IIa and IIx myofibers to lose its binding to the signaling receptor c‐met, thereby disturbing muscle homeostasis during aging. Here we show that rat anti‐HGF monoclonal antibody (mAb) 1H41C10, which was raised in‐house against a synthetic peptide FTSNPEVRnitroY198EV, a site well‐conserved in mammals, functions to confer resistance to nitration dysfunction on HGF. 1H41C10 was characterized by recognizing both nitrated and non‐nitrated HGF with different affinities as revealed by Western blotting, indicating that the paratope of 1H41C10 may bind to the immediate vicinity of Y198. Subsequent experiments showed that 1H41C10‐bound HGF resists peroxynitrite‐induced nitration of Y198. A companion mAb‐1H42F4 presented similar immuno‐reactivity, but did not protect Y198 nitration, and thus served as the control. Importantly, 1H41C10‐HGF also withstood Y250 nitration to retain c‐met binding and satellite cell activation functions in culture. The Fab region of 1H41C10 exerts resistivity to Y250 nitration possibly due to its localization in the immediate vicinity to Y250, as supported by an additional set of experiments showing that the 1H41C10‐Fab confers Y250‐nitration resistance which the Fc segment does not. Findings highlight the in vitro preventive impact of 1H41C10 on HGF nitration‐dysfunction that strongly impairs myogenic stem cell dynamics, potentially pioneering cogent strategies for counteracting or treating age‐related muscle atrophy with fibrosis (including sarcopenia and frailty) and the therapeutic application of investigational HGF drugs. [ABSTRACT FROM AUTHOR]

Aims: The urinary dysfunction in multiple system atrophy (MSA) is characterized by large post-void residuals (PVR) due to impaired bladder contractility. However, the evaluations of bladder contractility are not well validated in MSA. Because the bladder contractility index can be generally represented as Pdet Qmax (detrusor pressure at maximum urinary flow rate) + kQmax (maximum urinary flow rate), we aim to examine which "k" value is suitable for representing bladder contractility concerning its correlations to PVR and voided percentage (VOID%). Methods: We retrospectively reviewed 133 patients with MSA (74 males, 59 females, mean disease duration 3.2 years) who underwent an urodynamic study. We calculated bladder contractility using the formula PIPk = Pdet Qmax + kQmax by increasing the "k" value from 0.1 to 10 by increments of 0.1. We calculated the correlations between each PIPk (k = 0.1-10.0) and PVR and VOID%. Results: The correlational coefficients between PIPk and VOID% were larger than those between PIPk and PVR. The correlational coefficients between PIPk and VOID% reached a plateau level at a "k" value >5.0 in male patients, suggesting that currently used formulas such as Pdet Qmax + 5Qmax for males might be appropriate for male MSA patients. However, the correlational coefficients between PIPk and VOID% reached a plateau level in female patients when the "k" values were >6.0, which might overestimate bladder contractility in female patients. Conclusion: Although currently used formulas such as Pdet Qmax + 5Qmax might be appropriate for male MSA patients, formulas for female patients need further evaluation. [ABSTRACT FROM AUTHOR]

As effective treatments for sarcopenia other than exercise have not yet been established, research is needed on treatment methods using drugs that can control muscle atrophy. Therefore, in this study, we aimed to assess the use of intramuscular sustained-release drug delivery systems and direct intramuscular injection for the control of muscle atrophy. First, we evaluated the inhibitory effects of camphor on skeletal muscle atrophy in vitro. L6 skeletal muscle cells were analyzed by WST-1 cell viability, 3D tomographic lipid accumulation, and mitochondrial length. These results indicated that camphor significantly regulates L6 cell atrophy. Next, we established poly(lactic-co-glycolic acid) (PLGA)-based microspheres loaded with camphor (PLGA-camphor), with each PLGA-camphor microsphere have a size of ~ 66–75 μm. Camphor was released ~ 93.29% over 10 days. Finally, we administered the PLGA-camphor by intramuscular injection in the starved fed mice model and performed immunohistological and histological analyses. The results indicate that PLGA-camphor is able to significantly regulate skeletal muscle atrophy in vivo. Our results suggest that PLGA-camphor may affect skeletal muscle atrophy. In the present study, our research findings indicate that camphor significantly reduces muscle atrophy in vitro. It used gravity to load camphor into PLGA-based microspheres, which were 66–75 μm in size. The sustained release properties of PLGA-camphor microsphere were shown to release 93.29% of camphor over ten days. When directly injected into the muscle of mice with muscular dystrophy, the PLGA-camphor microsphere resulted in a noteworthy reduction in muscle atrophy, particularly in the starved-induced muscle atrophy model mice. Our results suggest that PLGA-camphor microsphere could be a promising method for addressing skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Impairments of object recognition are core features of neurodegenerative syndromes, in particular posterior cortical atrophy (PCA; the 'visual-variant Alzheimer's disease'). These impairments arise from damage to higher-level cortical visual regions and are often missed or misattributed to common ophthalmological conditions. Consequently, diagnosis can be delayed for years with considerable implications for patients. We report a new test for the rapid measurement of cortical visual loss – the Graded Incomplete Letters Test (GILT). The GILT is an optimised psychophysical variation of a test used to diagnose cortical visual impairment, which measures thresholds for recognising letters under levels of increasing visual degradation (decreasing "completeness") in a similar fashion to ophthalmic tests. The GILT was administered to UK Biobank participants (total n=2,359) and participants with neurodegenerative conditions characterised by initial cortical visual (PCA, n=18) or memory loss (typical Alzheimer's disease, n=9). UK Biobank participants, including both typical adults and those with ophthalmological conditions, were able to recognise letters under low levels of completeness. In contrast, participants with PCA consistently made errors with only modest decreases in completeness. GILT sensitivity to PCA was 83.3% for participants reaching the 80% accuracy cut-off, increasing to 88.9% using alternative cut-offs (60% or 100% accuracy). Specificity values were consistently over 94% when compared to UK Biobank participants without or with documented visual conditions, regardless of accuracy cut-off. These first-release UK Biobank and clinical verification data suggest the GILT has utility in both rapidly detecting visual perceptual losses following posterior cortical damage and differentiating perceptual losses from common eye-related conditions. [ABSTRACT FROM AUTHOR]

Vulvovaginal atrophy, characterized by the thinning of vaginal mucosa typically resulting from reduced estrogen levels, is frequently exacerbated by oncogynecologic treatments such as chemotherapy, hormonal therapy, radiotherapy, or surgery. This condition significantly impacts the quality of life for cancer survivors, leading to persistent discomfort, heightened infection risk, and negative effects on sexual function and self-esteem. Despite being a relatively common complication, vulvovaginal atrophy is not always discussed before the start of treatment. Treatments typically mirror those used for natural menopause; however, efficacy and safety data specific to this population are limited due to the exclusion of these patients from clinical trials. A major safety concern is the risk of hormone-sensitive cancer recurrence associated with estrogen therapy, which drives a preference for non-hormonal alternatives. Newer treatments, such as laser therapy, radiofrequency, and vaginal injections, show promise with minimal side effects and hormone-independent mechanisms, though efficacy data varies, highlighting the need for further research. This narrative review explores the epidemiology, risk factors, diagnosis, and management of vulvovaginal atrophy after the treatment for oncogynecologic disorders. [ABSTRACT FROM AUTHOR]

Background: Pain is a frequent yet poorly characterized symptom of multiple system atrophy (MSA). Understanding the factors influencing pain and its burden is crucial for improving the symptomatic treatment and quality of life of MSA individuals. Objective: This study aimed at assessing the prevalence, characteristics, and current treatment strategies for pain in MSA. Methods: A community‐based, online survey was conducted from February to May 2023. Invitations were extended to MSA individuals and informal MSA caregivers through patient advocacies and social media. Results: We included 190 persons with MSA and 114 caregivers. Eighty‐seven percent of MSA individuals reported pain, which was more prevalent among women (odds ratio [OR]: 6.38 [95% confidence interval, CI: 1.27–32.08], P = 0.025) and low‐income groups (OR: 5.02 [95% CI: 1.32–19.08], P = 0.018). Neck and shoulders (58%), back (45%), and legs (45%) were mostly affected. In the neck and shoulders, pain was associated with MSA core features, like orthostatic intolerance (OR: 4.80 [95% CI: 1.92–12.02], P = 0.001) and antecollis (OR: 3.24 [95% CI: 1.54–6.82], P = 0.002). Seventy‐six percent of individuals experiencing pain received treatment, mostly nonsteroidal anti‐inflammatory drugs (47%), acetaminophen (39%), and opioids (28%). Only 53% of respondents reported at least partial satisfaction with their current pain management. Pain mostly impacted work, household activities, and hobbies of MSA individuals, and caregivers' social activities. Conclusions: Pain is more prevalent than previously reported in MSA and particularly affects women and low‐income groups. Despite its frequency, pain management remains suboptimal, highlighting an urgent therapeutic need, likely entailing an optimized management of MSA core motor and non‐motor features. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]