Could tau-PET imaging contribute to a better understanding of the different patterns of clinical progression in Alzheimer's disease? A 2-year longitudinal study.

BACKGROUND: Monitoring the progression of Tau pathology makes it possible to study the clinical diversity of Alzheimer's disease. In this 2-year longitudinal PET study, we aimed to determine the progression of [18F]-flortaucipir binding and of cortical atrophy, and their relationships with cognitive decline. METHODS: Twenty-seven AD patients at the mild cognitive impairment/mild dementia stages and twelve amyloid-negative controls underwent a neuropsychological assessment, 3 T brain MRI, and [18F]-flortaucipir PET imaging (Tau1) and were monitored annually over 2 years with a second brain MRI and tau-PET imaging after 2 years (Tau2). We analyzed the progression of tau standardized uptake value ratio (SUVr) and grey matter atrophy both at the regional and voxelwise levels. We used mixed effects models to explore the relations between the progression of SUVr values, cortical atrophy, and cognitive decline. RESULTS: We found an average longitudinal increase in tau SUVr values, except for the lateral temporoparietal cortex where the average SUVr values decreased. Individual analyses revealed distinct profiles of SUVr progression according to temporoparietal Tau1 uptake: high-Tau1 patients demonstrated an increase in SUVr values over time in the frontal lobe, but a decrease in the temporoparietal cortex and a rapid clinical decline, while low-Tau1 patients displayed an increase in SUVr values in all cortical regions and a slower clinical decline. Cognitive decline was strongly associated with the progression of regional cortical atrophy, but only weakly associated with SUVr progression. CONCLUSIONS: Despite a relatively small sample size, our results suggest that tau-PET imaging could identify patients with a potentially "more aggressive" clinical course characterized by high temporoparietal Tau1 SUVr values and a rapid clinical progression. In these patients, the paradoxical decrease in temporoparietal SUVr values over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. They could particularly benefit from future therapeutic trials, the neuroimaging outcome measures of which deserve to be discussed.

Sequential Treatment With Topical Trifarotene and Injectable NASHA Gel in Acne Scars: A Case Series.

BACKGROUND: Topical retinoids are a mainstay in acne management and have been shown to improve skin texture. Injectable non-animal stabilized hyaluronic acid (NASHATM) gel as skin booster is largely used in aesthetic treatments to improve skin quality including the appearance of atrophic acne scars. OBJECTIVE: To evaluate a new sequential treatment with topical trifarotene and injectable skin booster NASHA gel in acne scars. METHODS: 10 patients between 19 and 25 years (3 males and 7 females) with previous moderate to severe acne vulgaris on the face with the outcome of atrophic and post-inflammatory slightly hyperpigmented scars were prescribed home short contact therapy (SCT) with topical trifarotene 50 μg/g at the evening for 3 months. A proper skincare routine for sensitive skin was also recommended. The 3-month retinoid therapy was followed by an injectable medical procedure with NASHA gel 20 mg/ml as skin booster. A minimum of 3 sessions to 10 sessions were carried out according to the severity of acne scars and the skin response observed. RESULTS: Adherence to the treatment was complete and the results evaluated by digital photography showed very effective results with high clinical improvement or almost complete resolution of atrophic acne scars. CONCLUSION: The results observed in this case series show that the sequential treatment with topical trifarotene and injectable NASHA gel as skin booster can be effective in the progressive reduction of acne scarring, potentially related to a synergic effect of skin remodeling and collagen stimulation. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7630.

Is occlusion of the main pancreatic duct by thermal ablation really safe? A surgical innovation assessed according to IDEAL recommendations.

INTRODUCTION: Pre-clinical studies suggest that thermal ablation of the main pancreatic duct (TAMPD) is more recommendable than glue for reducing postoperative pancreatic fistula (POPF). Our aims were (1) to analyze the changes in the pancreas of patients after TAMPD and (2) to correlate the clinical findings with those obtained from a study on an animal model. MATERIALS AND METHODS: A retrospective early feasibility study of a marketed device for a novel clinical application was carried out on a small number of subjects (n = 8) in whom TAMPD was conducted to manage the pancreatic stump after a pancreatectoduodenectomy (PD). Morphological changes in the remaining pancreas were assessed by computed tomography for 365 days after TAMPD. RESULTS: All the patients showed either Grade A or B POPF, which generally resolved within the first 30 days. The duct's maximum diameter significantly increased after TAMPD from 1.5 ± 0.8 mm to 8.6 ± 2.9 mm after 7 days (p = .025) and was then reduced to 2.6 ± 0.8 mm after 365 days PO (p < .0001). The animal model suggests that TAMPD induces dilation of the duct lumen by enzymatic digestion of ablated tissue after a few days and complete exocrine atrophy after a few weeks. CONCLUSIONS: TAMPD leads to long-term exocrine pancreatic atrophy by completely occluding the duct. However, the ductal dilatation that occurred soon after TAMPD could even favor POPF, which suggests that TAMPD should be conducted several weeks before PD, ideally by digestive endoscopy.

Electrical impedance myography detects age-related skeletal muscle atrophy in adult zebrafish.

Age-related deficits in skeletal muscle function, termed sarcopenia, are due to loss of muscle mass and changes in the intrinsic mechanisms underlying contraction. Sarcopenia is associated with falls, functional decline, and mortality. Electrical impedance myography (EIM)-a minimally invasive, rapid electrophysiological tool-can be applied to animals and humans to monitor muscle health, thereby serving as a biomarker in both preclinical and clinical studies. EIM has been successfully employed in several species; however, the application of EIM to the assessment of zebrafish-a model organism amenable to high-throughput experimentation-has not been reported. Here, we demonstrated differences in EIM measures between the skeletal muscles of young (6 months of age) and aged (33 months of age) zebrafish. For example, EIM phase angle and reactance at 2 kHz showed significantly decreased phase angle (5.3 ± 2.1 versus 10.7 ± 1.5°; p = 0.001) and reactance (89.0 ± 3.9 versus 172.2 ± 54.8 ohms; p = 0.007) in aged versus young animals. Total muscle area, in addition to other morphometric features, was also strongly correlated to EIM 2 kHz phase angle across both groups (r = 0.7133, p = 0.01). Moreover, there was a strong correlation between 2 kHz phase angle and established metrics of zebrafish swimming performance, including turn angle, angular velocity, and lateral motion (r = 0.7253, r = 0.7308, r = 0.7857, respectively, p < 0.01 for all). In addition, the technique was shown to have high reproducibility between repeated measurements with a mean percentage difference of 5.34 ± 1.17% for phase angle. These relationships were also confirmed in a separate replication cohort. Together, these findings establish EIM as a fast, sensitive method for quantifying zebrafish muscle function and quality. Moreover, identifying the abnormalities in the bioelectrical properties of sarcopenic zebrafish provides new opportunities to evaluate potential therapeutics for age-related neuromuscular disorders and to interrogate the disease mechanisms of muscle degeneration.

Unilateral pigmented paravenous retinochoroidal atrophy with acute angle-closure glaucoma: a case report.

BACKGROUND: Pigmented paravenous retinochoroidal atrophy (PPRCA) is an uncommon fundus disease characterized by perivenous aggregations of pigment clumps and retinochoroidal atrophy distributed along the retinal veins. We report a Chinese female case of unilateral PPRCA with acute angle-closure glaucoma (AACG). CASE PRESENTATION: A 50-year-old Chinese female presented with vision loss and elevated intraocular pressure (IOP) in the right eye and then underwent trabeculectomy. She referred to our clinic for further evaluation and treatment. The funduscopic examination revealed grayish retinochoroidal atrophy and osteocyte-like pigment clumping lesions along the retinal veins and peripapillary preretinal hemorrhage in the right eye. The patient also presented with AACG in the same eye on the basis of past medical history of acute attack, shallow anterior chamber depth (ACD), narrow angle showed by ultrasound biomicroscopy (UBM) and glaucomatous neuropathy identified by optical coherence tomography (OCT). Other examinations like fluorescein fundus angiography (FFA), electroretinogram (ERG) and electrooculography (EOG) all confirmed the aforementioned diagnose. CONCLUSION: PPRCA is a rare disease, uncommon in females and symmetrical in both eyes. We present a rare case of unilateral PPRCA accompanied with AACG.

[Prognostic factors and a customized approach to anti-VEGF therapy for exudative age-related macular degeneration. Analysis of the risk of macular atrophy development]. / Prognosticheskie faktory i kastomizirovannyi podkhod k anti-VEGF-terapii pri ekssudativnoi forme vozrastnoi makulyarnoi degeneratsii. Analiz riska vozniknoveniya makulyarnoi atrofii.

Age-related macular degeneration (AMD) is a chronic progressive multifactorial disease characterized by a degenerative process in the retinal pigment epithelium (RPE), Bruch's membrane and choriocapillaris of the fovea with secondary neuroepithelial (NE) damage. Intravitreal administration of drugs that inhibit VEGF is recognized as the only treatment for exudative form of AMD. Literature data is limited, and do not allow drawing conclusions about the influence of various factors (identified using OCT in the EDI mode) on the development of various subtypes of atrophy and their progression, so we decided to conduct our own study and research the possible timing and risks of developing various subtypes of macular atrophy in patients with exudative AMD receiving anti-VEGF therapy. As a result of the study, it was revealed that general macular atrophy (p=0.005) has a predominant effect on BCVA in the first year of the follow-up, while subtypes of atrophy anatomically less pronounced at one year of the follow-up manifest themselves only in the second year of the follow-up (p<0.05). Although color photography and autofluorescence are currently the only approved methods for assessing the degree of atrophy, the use of OCT may reveal reliable precursor endpoints that will facilitate and allow earlier and more accurate assessment of neurosensory tissue loss resulting from the atrophy. Thus, the development of macular atrophy is influenced by such parameters of disease activity as intraretinal fluid (p=0.006952), RPE detachment (p=0.001530) and the type of neovascularization (p=0.028860), as well as neurodenegerative changes in the form of drusen (p=0.011259) and cysts (p=0.042023). The new classification of atrophy according to the degree and localization of the lesion allows more differentiated conclusions about the effect of anti-VEGF drugs on the development of certain types of atrophy, which can be a decisive factor in determining the treatment tactics.

Optic Neuritis Related to Chronic Sphenoid Sinusitis as an Uncommon Cause of Vision Loss: A Case Report and Literature Review.

BACKGROUND Optic neuritis is a rare but possible complication of sphenoid sinusitis. CASE REPORT We present a case of a young woman with recurrent optic neuritis associated with chronic sphenoid sinusitis. A 29-year-old woman with visual impairment of the left eye to Snellen distance best-corrected visual acuity (DBCVA) of 0.5 and migraine headaches accompanied by vomiting and dizziness reported to the ophthalmic emergency room. The preliminary diagnosis was demyelinating optic neuritis. On head computed tomography, a polypoid lesion of the sphenoid sinus was found and qualified for elective endoscopic treatment. During a 4-year follow-up, evaluation of DBCVA, fundus appearance, visual field, ganglion cells layer (GCL), peripapillary retinal nerve fiber layer (RNFL) thickness, and ganglion cells and visual pathway function (pattern electroretinogram - PERG, pattern visual evoked potentials - PVEPs) were performed. Four years after the occurrence of the initial symptoms, surgical drainage of the sphenoid sinus was performed, which revealed a chronic inflammatory infiltrate and a sinus wall defect on the left side around the entrance to the visual canal. After surgery, headaches and other neurological symptoms resolved, but DBCVA deteriorated in the left eye to finger counting/hand motion, partial atrophy of the optic nerve developed, the visual field defect progressed to 20 central degrees, GCL and RNFL atrophy appeared, and deterioration of ganglion cells and visual pathway function were observed. CONCLUSIONS In patients with optic neuritis and atypical headaches, sphenoid sinusitis should be considered in the differential diagnosis. Delayed laryngological intervention can cause irreversible damage to the optic nerve.

Klf4 protects thymus integrity during late pregnancy.

Pregnancy causes abrupt thymic atrophy. This atrophy is characterized by a severe decrease in the number of all thymocyte subsets and qualitative (but not quantitative) changes in thymic epithelial cells (TECs). Pregnancy-related thymic involution is triggered by progesterone-induced functional changes affecting mainly cortical TECs (cTECs). Remarkably, this severe involution is rapidly corrected following parturition. We postulated that understanding the mechanisms of pregnancy-related thymic changes could provide novel insights into signaling pathways regulating TEC function. When we analyzed genes whose expression in TECs was modified during late pregnancy, we found a strong enrichment in genes bearing KLF4 transcription factor binding motifs. We, therefore, engineered a Psmb11-iCre : Klf4lox/lox mouse model to study the impact of TEC-specific Klf4 deletion in steady-state conditions and during late pregnancy. Under steady-state conditions, Klf4 deletion had a minimal effect on TEC subsets and did not affect thymic architecture. However, pregnancy-induced thymic involution was much more pronounced in pregnant females lacking Klf4 expression in TECs. These mice displayed a substantial ablation of TECs with a more pronounced loss of thymocytes. Transcriptomic and phenotypic analyses of Klf4 -/- TECs revealed that Klf4 maintains cTEC numbers by supporting cell survival and preventing epithelial-to-mesenchymal plasticity during late pregnancy. We conclude that Klf4 is essential for preserving TEC's integrity and mitigating thymic involution during late pregnancy.

The clinicopathological characteristics of gastric cancer and precancerous conditions in gastric DLBCL and MALT lymphoma patients: a multi-center retrospective study.

OBJECTIVE: The objective of this study is to explore the clinicopathological characteristics of gastric cancer and precancerous conditions in patients with primary gastric lymphoma. METHODS: We analyzed 474 cases of primary gastric lymphoma, mainly DLBCL and MALT, from three clinical centres retrospectively, and compared the clinicopathological parameters of primary gastric lymphoma patients complicated with gastric cancer, precancerous conditions, or with no complications. RESULTS: A total of 5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer, including metachronous gastric adenocarcinoma (3.2%) and synchronous gastric adenocarcinoma (1.9%). Of the patients with gastric lymphoma, 14.6% had precancerous conditions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%). Primary gastric lymphoma patients with an ulcerative type (p = 0.009) and Lugano classification stage IIE + IV (p < 0.001) lymphoma had a higher risk of complicating with gastric cancers or precancerous conditions. The rate of infection of Helicobacter pylori (Hp) was 68.4% in patients with primary gastric lymphoma, which was higher in patients with MALT lymphoma (p < 0.001), Lugano classification stage I + II (p < 0.001), and patients complicated with precancerous conditions and gastric cancer (p < 0.001), especially gastric cancer of the intestinal type (p = 0.04). Gastric cancer (95.8%) and precancerous conditions (91.3%) occurred mostly in Hp-infected primary gastric lymphoma patients, with a minor subset of Hp-eradicated patients. Primary gastric lymphoma patients had a higher detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population. CONCLUSIONS: Patients with primary gastric lymphoma have a high risk of developing gastric cancer and precancerous conditions, and this risk may be related to Helicobacter pylori infection. Follow-up of primary gastric lymphoma provides an opportunity for the detection of early gastric cancer.Key messages5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer.14.6% of the patients with gastric lymphoma had premalignant lesions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%).Primary gastric lymphoma patients complicating with gastric cancer had a higher infection rate of Helicobacter pylori (100.0%), a detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population.

Atrofia coriorretiniana pigmentada paravenosa de presentación unifocal y unilateral / Unifocal and unilateral pigmented paravenous retinochoroidal atrophy

La atrofia coriorretiniana pigmentada paravenosa es una entidad infrecuente, asociada a enfermedades autoinmunes y otras complicaciones oculares, generalmente multifocal, bilateral y simétrica. Se presenta el caso clínico de una paciente con artritis reumatoide que acude por dolor de varios días. Presenta disminución de agudeza visual de ojo izquierdo, escleritis nodular y atrofia coriorretiniana con acumulación de pigmento en espículas óseas en arcada vascular temporal inferior y agujero macular lamelar. El ojo derecho no presenta alteraciones. La autofluorescencia del ojo izquierdo muestra hipoautofluorescencia de bordes definidos en la lesión. La angiografía con fluoresceína evidencia hiperfluorescencia compatible con degeneración del epitelio pigmentario retiniano y bloqueo en las áreas de pigmento. El campo visual revela un defecto altitudinal en hemicampo superior. Este caso describe una atrofia coriorretiniana pigmentada paravenosa atípica unifocal y unilateral. Se debe conocer esta variante para realizar un correcto diagnóstico diferencial, así como proporcionar una información pronóstica adecuada (AU)

Paravenous pigmented chorioretinal atrophy is a generally multifocal, bilateral and symmetric rare entity associated with autoimmune diseases and other ocular complications. We present the clinical case of a patient with rheumatoid arthritis who attended for pain of several days. He presented decreased visual acuity of the left eye, nodular scleritis and chorioretinal atrophy with pigment accumulation in bone spicules in the inferior temporal vascular arcade and lamellar macular hole. The right eye shows no alterations. LE autofluorescence shows a hypoautofluorescence lesion with defined edges. Fluorescein angiography shows hyperfluorescence consistent with retinal pigmentary epithelial degeneration and blockage in pigment areas. The visual field reveals a defect in the superior hemifield. This case describes an atypical unifocal and unilateral paravenous pigmented chorioretinal atrophy. This variant must be known to make a correct differential diagnosis, as well as to provide adequate prognostic information (AU)

Ursodeoxycholic Acid Binds PERK and Ameliorates Neurite Atrophy in a Cellular Model of GM2 Gangliosidosis.

The Unfolded protein response (UPR), triggered by stress in the endoplasmic reticulum (ER), is a key driver of neurodegenerative diseases. GM2 gangliosidosis, which includes Tay-Sachs and Sandhoff disease, is caused by an accumulation of GM2, mainly in the brain, that leads to progressive neurodegeneration. Previously, we demonstrated in a cellular model of GM2 gangliosidosis that PERK, a UPR sensor, contributes to neuronal death. There is currently no approved treatment for these disorders. Chemical chaperones, such as ursodeoxycholic acid (UDCA), have been found to alleviate ER stress in cell and animal models. UDCA's ability to move across the blood-brain barrier makes it interesting as a therapeutic tool. Here, we found that UDCA significantly diminished the neurite atrophy induced by GM2 accumulation in primary neuron cultures. It also decreased the up-regulation of pro-apoptotic CHOP, a downstream PERK-signaling component. To explore its potential mechanisms of action, in vitro kinase assays and crosslinking experiments were performed with different variants of recombinant protein PERK, either in solution or in reconstituted liposomes. The results suggest a direct interaction between UDCA and the cytosolic domain of PERK, which promotes kinase phosphorylation and dimerization.

Prevalence and associated health and lifestyle factors of myopic maculopathy in northern China: the Kailuan eye study.

BACKGROUND: To evaluate the prevalence and associated health and lifestyle factors of myopic maculopathy (MM) in a northern Chinese industrial city. METHODS: The cross-sectional Kailuan Eye Study included subjects who participated in the longitudinal Kailuan Study in 2016. Ophthalmologic and general examinations were performed on all the participants. MM was graded based on fundus photographs using the International Photographic Classification and Grading System. The prevalence of MM was evaluated. Univariate and multiple logistic regression were adopted to evaluated risk factors of MM. RESULTS: The study included 8330 participants with gradable fundus photographs for MM and ocular biometry data. The prevalence of MM was 1.11% (93/8330; 95% confidence interval [CI] 0.89-1.33%). Diffuse chorioretinal atrophy, patchy chorioretinal atrophy, macular atrophy, and plus lesions were observed in 72 (0.9%), 15 (0.2%), 6 (0.007%), and 32 eyes (0.4%), respectively. MM was more common in eyes with longer axial length (OR 4.517; 95%CI 3.273 to 6.235) and in participants with hypertension (OR 3.460; 95%CI 1.152 to 10.391), and older age (OR 1.084; 95%CI 1.036 to 1.134). CONCLUSIONS: The MM was present in 1.11% of the northern Chinese individuals 21 years or older and the associate factors include longer axial length, older age, and hypertension.

Visualization of Short Posterior Ciliary Artery Insertion Due to Posterior Staphyloma and Myopic Chorioretinal Atrophy.

This case report describes the visualization of a short posterior ciliary artery insertion as a result of posterior staphyloma and chorioretinal atrophy in a patient in their 50s with pathologic myopia.

Buccally or Lingually Tilted Implants in the Lateral Atrophic Mandible: A Three-Year Follow-Up Study Focused on Neurosensory Impairment, Soft-Tissue-Related Impaction and Quality of Life Improvement.

Background and Objectives: In the severely resorbed posterior mandible, implant placement requires either bone regenerative procedures, subperiosteal implants or short implant placement with drawbacks including morbidity and increased treatment costs and duration. To overcome these inconveniences, some unconventional alternatives have been suggested, such as buccally or lingually tilted implants in the lateral mandible, bypassing the inferior alveolar nerve. The aim of the present retrospective study was to evaluate the three-year survival rate of implants inserted in the posterior atrophic mandible, bypassing the inferior alveolar nerve. The assessment was focused on the occurrence of postoperative complications related to neurosensory impairment and soft tissue impaction, as well as overall improvement in quality of life. Materials and Methods: Patients with severe bone atrophy in the lateral area of the mandible were included in the present study. Only the implants tilted either buccally or lingually to bypass the inferior alveolar nerve were analysed. The relation between peri-implant soft tissue and the healing abutment was assessed and a secondary revision surgery was performed when indicated. The Semmes-Weinstein pressure neurological test was used for qualitative assessment of inferior alveolar nerve function and the Geriatric Oral Health Assessment Index (GOHAI) was used for evaluating Oral-Health-Related Quality of Life (OHRQoL). Results: Fourteen implants were placed in nine patients during the evaluation period. Survival rate was 100%, temporary paraesthesia occurred in one patient and a limited definitive paraesthesia was seen in another patient. Mild or significant discomfort related to soft tissue impaction with healing abutment was observed in six out of nine patients. A statistically significant OHRQoL improvement was observed in all patients. Conclusions: Despite the limited number of patients and observation time, insertion of implants buccally or lingually bypassing the inferior alveolar nerve is a predictive treatment option for patients with severe bone atrophy in the posterior mandible.

Metabolomic Profiling of Asparagine Deprivation in Asparagine Synthetase Deficiency Patient-Derived Cells.

The natural amino acid asparagine (Asn) is required by cells to sustain function and proliferation. Healthy cells can synthesize Asn through asparagine synthetase (ASNS) activity, whereas specific cancer and genetically diseased cells are forced to obtain asparagine from the extracellular environment. ASNS catalyzes the ATP-dependent synthesis of Asn from aspartate by consuming glutamine as a nitrogen source. Asparagine Synthetase Deficiency (ASNSD) is a disease that results from biallelic mutations in the ASNS gene and presents with congenital microcephaly, intractable seizures, and progressive brain atrophy. ASNSD often leads to premature death. Although clinical and cellular studies have reported that Asn deprivation contributes to the disease symptoms, the global metabolic effects of Asn deprivation on ASNSD-derived cells have not been studied. We analyzed two previously characterized cell culture models, lymphoblastoids and fibroblasts, each carrying unique ASNS mutations from families with ASNSD. Metabolomics analysis demonstrated that Asn deprivation in ASNS-deficient cells led to disruptions across a wide range of metabolites. Moreover, we observed significant decrements in TCA cycle intermediates and anaplerotic substrates in ASNS-deficient cells challenged with Asn deprivation. We have identified pantothenate, phenylalanine, and aspartate as possible biomarkers of Asn deprivation in normal and ASNSD-derived cells. This work implies the possibility of a novel ASNSD diagnostic via targeted biomarker analysis of a blood draw.

[Personalized treatment options for spinal muscular atrophy]. / A spinalis izomatrophia személyre szabott terápiás lehetoségei.

Spinal muscular atrophy (SMA) is an autosomal recessive disease leading to progressive muscle weakness and atrophy, in severe cases also affecting the bulbar and respiratory muscles.The clinical spectrum of the disease is extremely variable, in the most severe cases resulting in perinatal death, while at the least severe end of the spectrum causing some motor deficits in old age without the loss of ambulation. Spinal muscular atrophy care has changed dramatically in recent years due to the availability of new therapeutic options. 
The FDA approved nusinersen in 2016, this was followed by the approval of onasemnogene abeparvovec in 2019 and risdiplam in 2020. The EMA approved all three therapies a year later. Two of the threapies work at the pre-mRNA level, one at the DNA level. The clinical studies leading to the approval of the three drugs included patients of different ages and clinical conditions, and utilised partly different motor and functional scales. Therefore, direct comparison of these clinical studies is not possible. However, an increasing amount of real-world data contribute to the better understanding of the efficacy of the different therapies for patients of different ages and clinical conditions, in a real-world setting. Thus, the question may arise “Which is the best SMA therapy?”. This is an impossible question to answer. Indeed the question “Which therapy is the most suitable for a certain patient at a certain time?” is much more realistic. Here, we provide a brief overview of the objectively measurable results of the three therapies to date and an outlook into future therapeutic avenues. 

Baseline structural MRI and plasma biomarkers predict longitudinal structural atrophy and cognitive decline in early Alzheimer's disease.

BACKGROUND: Crucial to the success of clinical trials targeting early Alzheimer's disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers. METHODS: Longitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into ß-amyloid positive/negative (Aß+/Aß-)] subgroups. Baseline plasma (p-tau181 and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aß+/Aß- subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement. RESULTS: A total of 245 CN (35.0% Aß+) and 361 MCI (53.2% Aß+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aß+ and Aß- subgroups, including Aß- CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI [area under the curve (AUC): 0.78-0.93] and more modestly in CN (0.65-0.73). CONCLUSIONS: The present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aß- CN indicates the potential use of these biomarkers in predicting a normal age-related decline.