ALS Cases Research Articles

6794 Primary Adrenal Insufficiency Following Bilateral Adrenal Hemorrhage Secondary To Antiphospholipid Syndrome

Abstract Disclosure: M. Alameri: None. A.M. Alnuaimi: None. Y. Alabrach: None. A. Abbas: None. S. Baroud: None. M. El Khazendar: None. Introduction: Adrenal insufficiency (AI) is a rare life-threatening complication of antiphospholipid antibody syndrome (APS) accounting for 0.4% to 0.5% of Al cases. Case report: A 26-year-old female with background history of primary antiphospholipid syndrome (PAPS) presented with 3 weeks history of dull abdominal pain and fatigue. Examination revealed dehydration, orthostatic hypotension and hyperpigmented skin. Biochemistry assessment was consistent with primary adrenal insufficiency (hyponatremia 125 mol/L, hyperkalaemia 6.8 mmol/L, low random cortisol 142 mol/L, high ATCH 440 pmol/L [N 1.6-13.9], low aldosterone <1.05 ng/dL and high renin 128 ng/L [N 4-23.7]). She received 100mg hydrocortisone followed by regular IV hydrocortisone q6hrs. CT abdomen revealed bilaterally enlarged hyperdense adrenal glands suggestive of haemorrhage. Adrenal MRI confirmed subacute bilateral adrenal haemorrhage (BAH) replacing whole adrenal glands with hemosiderin depositions and calcifications without evidence of underlying tumor. Anti-21-hydroxylase antibody came back negative. She was discharged on hydrocortisone, fludrocortisone and hydroxychloroquine. Education was given for sick days rule and hydrocortisone emergency kit was provided for adrenal crisis. Discussion and conclusion: We describe a patient with APS, who developed Al due to bilateral subacute adrenal haemorrhages. Adrenal haemorrhage is rare but life-threatening complication of APS. High clinical vigilance is important to consider adrenal haemorrhage in differential diagnosis of Al, specifically in patients with known antiphospholipid antibody syndrome (APS). Presentation: 6/3/2024

Psychiatric symptoms and TDP-43 pathology in amyotrophic lateral sclerosis

BackgroundALS is not a pure motor neuron disease but co-occurs with cognitive impairment and psychiatric symptoms. The neuropathological origin of the psychiatric symptoms is unclear. This study examined the association between the psychiatric symptoms and neuropathology of ALS. MethodsWe investigated the clinicopathological characteristics of 15 autopsy cases of ALS, including neuronal loss, gliosis, and the burden of TDP-43 pathology. We divided TDP-43–positive structures by morphology into four categories (neuronal cytoplasmic inclusion, dystrophic neurite, dot, and glial cytoplasmic inclusion) and gave each a semiquantitative score in nine brain regions. Braak neurofibrillary tangle stage, Thal amyloid phase, Lewy-related pathology, and argyrophilic grains were also assessed. ResultsOf the 15 ALS patients, seven had presented with psychiatric symptoms and eight had not. Significantly higher TDP-43 pathology scores were found in the group with psychiatric symptoms in the temporal tip, transentorhinal cortex, entorhinal cortex, subiculum, and the hippocampal CA1 region and dentate gyrus. Cognitive impairment was not significantly associated with the degree of TDP-43 pathology. There were no significant differences in the degree of neuronal loss/gliosis or in other concurrent pathologies between patients with and without psychiatric symptoms. Morphological evaluation showed that neuronal cytoplasmic inclusions, dystrophic neurites, and dots tended to be more common in the group with psychiatric symptoms. ConclusionPsychiatric symptoms in ALS may be related to TDP-43 pathology in the perforant pathway. (224 words).

Cognitive assessment of a sample of Egyptian patients with amyotrophic lateral sclerosis

BackgroundCognitive and behavioral changes in ALS are featured as an integral part of the disease. A noticeable proportion of ALS patients present with a full-blown picture of frontotemporal dementia, which is considered the most common form of cognitive impairment in ALS.ResultsA total of 30 ALS cases and 30 sex, age and education matched healthy controls were enrolled; their sociodemographic data were statistically insignificant as regards (age, sex, education). Regarding cognitive and behavioral assessment using the ECAS-EG, both ECAS mean total score and subdomains mean scores were significantly lower in ALS patients compared to controls (p-value < 0.001), with statistically significant relation between ALS clinical staging and ECAS total scores (p-value < 0.001). Furthermore, it was found that mean scores of nearly all ECAS domains are lower in early-onset group with longer duration of illness than late onset with short duration of illness but with a non-statistically significant difference.ConclusionALS causes significant cognitive impairment, with relation between functional status and clinical staging of the disease with the severity of cognitive and behavioral dysfunctions and although early-onset cases had lower score on ECAS compared to those with late onset, but it was non-significant.

Investigations on the crystallographic stacking disordering and properties of novel Ga-containing in-plane chemically ordered (Cr2/3R1/3)2GaC (R=Y, Tb - Lu) i-MAX phases

Eight novel transition metal carbides, nanolaminated (Cr2/3R1/3)2GaC (R=Y, Tb, Dy, Ho, Er, Tm, Yb and Lu) with R in-plane chemical ordered occupation, have been synthesized with mainly Cmcm orthorhombic structure and monotonously decreased lattice parameters due to lanthanide contraction. Stacking disorderings and high-density slidings within c plane have been observed. Two characteristic in-plane sliding, along [100] or [1¯30]o directions have been analyzed with former one leading into the structural evolution between Cmcm and C2/c symmetry. Such an atomic scale co-existence of Cmcm and C2/c structures is explained by more negative charge for Ga and anisotropic bonding with Ga compared with A=Al case. Thus, the Vickers hardness, fracture strength and increased wear depth are reduced in representative (Cr2/3Lu1/3)2GaC i-MAX bulk compared with the (Cr2/3Lu1/3)2AlC counterpart.

Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.

CHCHD10 is mutated in rare cases of FTD and ALS and aggregates in mouse models of disease. Here we show that the disordered N-terminal domain of CHCHD10 forms amyloid fibrils and report their cryoEM structure. Disease-associated mutations cannot be accommodated by the WT fibril structure, while sequence differences between CHCHD10 and CHCHD2 are tolerated, explaining the co-aggregation of the two proteins and linking CHCHD10 and CHCHD2 amyloid fibrils to neurodegeneration.

Usefulness of the one-step technique in functional end-to-end anastomosis for colonic surgery: results of a prospective multicentre cohort study from the Japanese KYCC group.

Although functional end-to-end anastomosis (FEEA) using a stapler in the colorectal field has been recognised worldwide, the technique varies by surgeon, and the safety of anastomosis using different techniques is unknown. This multicentre prospective observational cohort study was conducted by the KYCC Study Group in Yokohama, Japan, and included patients who underwent colonic resection at seven centres between April 2020 and March 2022. This study compared the incidence of surgery-related abdominal complications (SAC: anastomotic leakage [AL], anastomotic bleeding, intra-abdominal abscess, enteritis, ileus, surgical site infection, and other abdominal complications) between two different methods of FEEA (one-step [OS] method: simultaneous anastomosis and bowel resection; two-step [TS] method: anastomosis after bowel resection). Complications of Clavien-Dindo classification grade2 or higher were assessed. Among 293 eligible cases, the OS and TS methods were used in 194 (66.2%) and 99 (33.8%) patients, respectively. The baseline characteristics were similar between the groups. The OS method used fewer staplers (three vs. four staplers, p < 0.00001). There were no significant differences in SAC rate between the OS (19.1%) and the TS (16.2%) groups (p = 0.44). The OS group had four cases (2.1%) of AL (two patients; grade3, two patients; grade2) while the TS group had one case (1.0%) of grade2 AL (p = 0.67). Multivariate logistic regression analysis showed that male sex (odds ratio [OR] 3.95; p < 0.00001), an open surgical approach (OR 2.36; p = 0.03), and longer operative duration (OR,2.79; p = 0.002) were independent predictors of complications, whereas the OS method was not an independent predictor (OR 1.17; p = 0.66). The OS and the TS technique for stapled colonic anastomosis in a FEEA had a similar postoperative complication rate. UMIN000039902 (registration date 23 March 2020).

Prevalence of ALS in all 50 states in the United States, data from the National ALS Registry, 2011–2018

Objective: To summarize the prevalence of ALS in all 50 states and Washington, DC in the United States from 2011 to 2018 using data collected and analyzed by the National ALS Registry. In October 2010, the federal Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally mandated Registry to determine the incidence and prevalence of ALS within the USA, characterize the demographics of persons with ALS, and identify the potential risk factors for the disease. This is the first analysis of state-level ALS prevalence estimates. Methods: ALS is not a notifiable disease in the USA, so the Registry uses a two-pronged approach to identify cases. The first approach uses existing national administrative databases (Medicare, Veterans Health Administration, and Veterans Benefits Administration). The second method uses a secure web portal to gather voluntary participant data and identify cases not included in the national administrative databases. Results: State-level age-adjusted average prevalence from 2011–2018 ranged from 2.6 per 100,000 persons (Hawaii) to 7.8 per 100,000 persons (Vermont), with an average of 4.4 per 100,000 persons in the US. New England and Midwest regions had higher prevalence rates than the national average. Conclusions: These findings summarize the prevalence of ALS for all 50 states from 2011 to 2018. This is a continuing effort to identify ALS cases on a national population basis. The establishment of the National ALS Registry has allowed for epidemiological trends of this disease and the assessment of potential risk factors that could cause ALS.

TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy.

Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined. A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel. The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/TARDBP). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that TARDBP mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including C9ORF72 or SOD1, are respectively absent or rare in FOSMN. FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically TARDBP should be considered in patients with FOSMN.

Rurality modifies the association between symptoms and the diagnosis of amyotrophic lateral sclerosis

Objective We utilized national claims-based data to identify the change in odds of diagnosis of ALS following possible-ALS-symptoms-and whether the change varies in urban/rural areas. Methods Insurance claims were obtained from the Merative MarketScan databases, 2001–2021 in the United States. Individuals with incident ALS were identified and matched on age, sex, and enrollment period to individuals without ALS. For all individuals, claims for 8 possible-ALS-symptoms in the time before any ALS diagnosis were identified. We then used conditional logistic regression to estimate the odds of being diagnosed with ALS following these symptoms and whether the association varied by urban/rural location. Results 19,226 individuals with ALS were matched to 96,126 controls. Patients with ALS were more likely to live in an urban area (87.0% vs 84.5%). Of those with ALS 84% had 1+ of our 8 possible-ALS-symptom compared to 51% of controls. After adjustment for confounders, having possible-ALS-symptoms increased the odds of a future ALS diagnosis by nearly 5-fold. A dose-response pattern was present with increasing odds as the number of symptoms increased. In all models, urban areas were associated with increased odds of diagnosis with ALS while the effect of having a symptom was smaller in urban places. Urban cases of ALS are diagnosed at younger ages. Conclusions These results suggest symptoms may appear and be noted years before the diagnosis of ALS. Additionally, rural patients are diagnosed at later ages with a greater dependence on symptoms than urban patients. These results highlight potential improvements for screening for ALS.

Functional consequences of familial ALS-associated SOD1L84F in neuronal and muscle cells.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by progressive skeletal muscle denervation and loss of motor neurons that results in muscle atrophy and eventual death due to respiratory failure. Previously, we identified a novel SOD1L84F variation in a familial ALS case. In this study, we examined the functional consequences of SOD1L84F overexpression in the mouse motor neuron cell line (NSC-34). The cells expressing SOD1L84F showed increased oxidative stress and increased cell death. Interestingly, SOD1L84F destabilized the native dimer and formed high molecular weight SDS-resistant protein aggregates. Furthermore, SOD1L84F also decreased the percentage of differentiated cells and significantly reduced neurite length. A plethora of evidence suggested active involvement of skeletal muscle in disease initiation and progression. We observed differential processing of the mutant SOD1 and perturbations of cellular machinery in NSC-34 and muscle cell line C2C12. Unlike neuronal cells, mutant protein failed to accumulate in muscle cells probably due to the activated autophagy, as evidenced by increased LC3-II and reduced p62. Further, SOD1L84F altered mitochondrial dynamics only in NSC-34. In addition, microarray analysis also revealed huge variations in differentially expressed genes between NSC-34 and C2C12. Interestingly, SOD1L84F hampered the endogenous FUS autoregulatory mechanism in NSC-34 by downregulating retention of introns 6 and 7 resulting in a two-fold upregulation of FUS. No such changes were observed in C2C12. Our findings strongly suggest the differential processing and response towards the mutant SOD1 in neuronal and muscle cell lines.

A proteomic atlas of kidney amyloidosis provides insights into disease pathogenesis

The mechanisms of tissue damage in kidney amyloidosis are not well described. To investigate this further, we used laser microdissection-mass spectrometry to identify proteins deposited in amyloid plaques (expanded proteome) and proteins overexpressed in plaques compared to controls (plaque-specific proteome). This study encompassed 2650 cases of amyloidosis due to light chain (AL), heavy chain (AH), leukocyte chemotactic factor-2-type (ALECT2), secondary (AA), fibrinogen (AFib), apo AIV (AApoAIV), apo CII (AApoCII) and 14 normal/disease controls. We found that AFib, AA, and AApoCII have the most distinct proteomes predominantly driven by increased complement pathway proteins. Clustering of cases based on the expanded proteome identified two ALECT2 and seven AL subtypes. The main differences within the AL and ALECT2 subtypes were driven by complement proteins and, for AL only, 14-3-3 family proteins (a family of structurally similar phospho-binding proteins that regulate major cellular functions) widely implicated in kidney tissue dysfunction. The kidney AL plaque-specific proteome consisted of 24 proteins, including those implicated in kidney damage (α1 antitrypsin and heat shock protein β1). Hierarchical clustering of AL cases based on their plaque-specific proteome identified four clusters, of which one was associated with improved kidney survival and was characterized by higher overall proteomic content and 14-3-3 proteins but lower levels of light chains and most signature proteins. Thus, our results suggest that there is significant heterogeneity across and within amyloid types, driven predominantly by complement proteins, and that the plaque protein burden does not correlate with amyloid toxicity.

Prevalence, Incidence, and Characterization of LIGHT Chain Amyloidosis in the USA: A Real-World Analysis Utilizing Electronic Health Records (EHR)

Background: Light chain (AL) amyloidosis is a rare disease characterized by the deposition of misfolded immunoglobulin light chains, resulting in organ dysfunction and significant morbidity and mortality. However, population-based studies on the epidemiology of AL are limited. This study aimed to provide an up-to-date assessment of the prevalence and incidence of AL, examine temporal changes in prevalence over a 5-year period, and characterize the AL population in the USA. Methods: A retrospective analysis was conducted using de-identified patient records from Optum's Clinical Electronic Health Record (EHR) database (&amp;gt;140,000 providers and &amp;gt;60 million unique patients). Adults with AL were identified based on ≥2 diagnosis codes (ICD-10-CM code E85.81) or positive mentions about the disease (including clinical features indicative of AL) found in the physician's notes (≥30 days apart). Patients with clinical data at least 12 months pre- index event (defined as the date of the first AL amyloidosis diagnosis or positive mention during the identification period: January 01, 2017 - December 31, 2021) were included in the analysis. Prevalence estimates were calculated for each year between 2017 and 2021, and annual percentage changes were assessed to determine temporal trends. Annual incidence was calculated as the number of newly diagnosed AL cases occurring each year between 2019 and 2021. Additionally, patient demographics, comorbidities, and Mayo 2004 staging with European modification (based on availability of the cardiac biomarkers: NT-proBNP and troponin) were characterized at index date or in the 12-month post index period. Results: A total of 1471 AL patients were included in the study population. The mean age of the prevalent patients was 67.2 years, with 54.5% being male. Most patients were White (78.5%), followed by Black (14.5%), Hispanic (3.3%), Asian (1.2%), and other/unknown (2.6%). The diagnosed prevalence of AL substantially increased from 22.7 to 69.1 cases per million between 2017 and 2021, with an annual growth rate of 32.1%. In 2021, the annual incidence of AL was estimated to be 16.7 patients per million in the general population, with an annual growth rate of 7.7% since 2019, at which time incidence was 14.4 patients per million. The distribution of patients by Mayo stage at diagnosis among those with available biomarker information (n=613, 42% of total sample) was: Stage I, 27%; Stage II, 42%; Stage IIIa, 16%; and Stage IIIb, 15%. The most prevalent comorbidities reported in the year after diagnosis were hypertension (56.6%), dyslipidaemia (51.7%), chronic kidney disease (41.3%), multiple myeloma and malignant plasma cell neoplasms (37.5%), and heart failure (34.5%). Cardiomyopathy was observed in 40.2% of the AL patients. Conclusions: This study provides an updated report of the prevalence and incidence of AL using a large-scale EHR database. The observed rise in AL prevalence and incidence is likely due to a combination of increased disease awareness and improvements in detection and management. The number of comorbidities, especially those related to cardiac function, suggest a continuing unmet need for more therapeutic options. Furthermore, the Mayo stage distribution of patients highlights the need for enhanced efforts to diagnose AL earlier due to the high mortality associated with advanced Mayo stages. These epidemiological findings reinforce the importance of continuous monitoring of prevalence, incidence trends, and the burden of AL in the US.

Pronunciation Flaws and Proper Recitation Measures According to Early Tajwīd Sources: The Case of al- Qurṭubī and Ibn al-Bannāʾ

Telaffuz kusurları, Kur’an lafızlarının farklı şekillerde telaffuzuna konu olması sebebiyle dil, edebiyat ve tecvid âlimleri nezdinde önemli bir yere sahip olmuştur. Bu çerçevede tecvid âlimleri erken dönemlerden itibaren telaffuz kusurlarının tespitine yönelmişler, bunlarla ilgili eserler kaleme almışlardır. Onların bu noktadaki amaçlarını, yanlış telaffuzlara dikkat çekerek sahih tilâvet tarzını korumak şeklinde yorumlamak mümkündür. Tecvid âlimlerinin fe’fee, temteme, keşkeşe, ʿan‘ane, ter‘îd, teşdîk, temdîğ, tatrîb gibi ses, lehçe ve konuşma kaynaklı ortaya çıkan telaffuz kusurlarını, genellikle erken dönem dilbilimsel kaynaklardan tespit ettikleri anlaşılmaktadır. Ancak tespitle birlikte yeni tanımlamalara gitmeleri, kendi dönem ve zaviyelerine göre bu kusurları gidermeye yönelik çözüm önerileri sunmaları, onları dilbilimsel kaynaklardan ayıran en önemli özellik olmuştur. Bu durum onların bu olguya yönelik derinlikli bir bakış açısına sahip olduklarının da açık bir göstergesidir. Ne var ki, tecvid âlimlerinin asırlar öncesinde gündemlerine aldıkları bu olgu, sonraki süreçlerde beklenen ölçüde araştırmalara konu olmamıştır. Ülkemizde de konuyla ilgili makale düzeyinde herhangi bir çalışmanın yapılmaması, konunun detaylı bir şekilde incelenmesini gerek-tirmektedir. Bu makale, Abdülvehhâb el-Kurtubî’nin (ö. 462/1070) el-Mûdıh fi’t-tecvîd’i ile İbnü’l-Bennâ el-Bağdâdî’nin (ö. 471/1079) Beyânü’l-ʿuyûb’u özelinde erken dönem tecvid kaynaklarında geçen telaffuz kusurlarının tespitini, tanımını ve müellifler veçhesinden dile getirilen çözüm önerilerinin analizini yapmayı amaçlamıştır. Ses, lehçe ve konuşma kaynaklı telaffuz kusurları hakkında İbnü’l-Bennâ’nın müstakil bir eser yazması, Kurtubî’nin ise kitabının son bölümünü bu konuya tahsis etmesi, bu hususta ilgili müelliflerin tercih edilmesindeki temel sebep olmuştur. Ayrıca makale bu açıklamalar ışığında düzgün tilâvet ölçülerinin ortaya çıkarmayı da hedeflemiştir. Konu ve kavramlar, erken dönem dilbilimsel kaynaklarının yanı sıra, erken dönem tecvid kaynaklarıyla da mukayeseli bir şekilde işlenmiştir. Makalede sosyal bilimlerde sıkça takip edilen tespit, tanımlama ve mukayese yöntemleri kullanılmıştır.

A Comparative Study of Deep Learning Approaches for Amyotrophic Lateral Sclerosis Super-Resolution Image Classification

Amyotrophic lateral sclerosis is a fatal degenerative neurological disease known as motor neuron disease. According to research, amyotrophic lateral sclerosis affects nerve cells related to movement in the brain and spinal cord, leading to the death of motor neurons, making the brain unable to control muscle movement, and resulting in a significant loss of motor nerve cells, leading to muscle atrophy. In the early stages of ALS, symptoms are mild, often go unnoticed, and can easily be confused with other diseases. Patients may only feel symptoms such as weakness, convulsions, and fatigue, gradually develop muscle atrophy all over the body, difficulty swallowing, and finally die of respiratory failure. TDP-43 is a DNA/RNA binding protein typically located in the nucleus regulating various steps of RNA metabolism. Meanwhile, TDP-43 is the most prominent pathological protein in the characteristics of ALS patients.[1] TDP-43 is depleted in the nucleus in nearly all ALS cases but accumulates in the cytoplasm.Deep learning is learning the internal laws and representation levels of sample data. The information obtained from these learning processes can significantly help interpret data such as text, images, and sounds. Its goal is to enable machines to analyze and learn like humans and recognize data. Additionally, super-resolution microscopy can be used to observe the conformation of proteins in biological samples, thereby gaining insight into the structure and assembly mechanism of TDP-43 aggregates.This project aims to use super-resolution images for machine learning to build a model for classifying ALS patients from non-ALS patients. At the same time, multiple neural network models are used for training and then compared to select the model with the highest accuracy.

Prevalence of amyotrophic lateral sclerosis in the United States, 2018

Objective To estimate prevalent ALS cases in the United States for calendar year 2018. Methods The National ALS Registry (Registry) compiled data from national administrative databases (from the Centers for Medicare and Medicaid Services, the Veterans Health Administration, and the Veterans Benefits Administration) and enrollment data voluntarily submitted through a web portal (www.cdc.gov/als). We used log-linear capture-recapture (CRC) model-based methodology to estimate the number of cases not ascertained by the Registry. Results The Registry identified 21,655 cases of ALS in 2018, with an age-adjusted prevalence of 6.6 per 100,000 U.S. population. When CRC methods were used, an estimated 29,824 cases were identified, for an adjusted prevalence of 9.1 per 100,000 U.S. population. The demographics of cases of ALS did not change from previous year’s reports. ALS continues to impact Whites, males, and persons over 50 years of age more so than other comparison groups. The results from the present report suggest case ascertainment for the Registry has improved, with the estimate of missing prevalent cases decreasing from 44% in 2017 to 27% in in 2018. Discussion Consistent with previous estimates that used CRC, ALS prevalence in the United States is about 29,824 cases per year.

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France

BackgroundEarly cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AimTo reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. MethodsThis was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. ResultsOverall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010–2012 to 308 in 2019–2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013–2014 to 45.9% in 2019–2020). Lastly, among patients diagnosed with ATTRv in 2019–2020, 83.9% had ATTR Val122Ile cardiac phenotype. ConclusionsThis study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

Proteomic investigation of ALS motor cortex identifies known and novel pathogenetic mechanisms

The key pathological feature in ALS is death of motor neurones from the brain and spinal cord, but the molecular mechanisms underlying this degeneration remain unknown. Quantifying the motor cortex proteome in autopsy brain and comparing tissues from ALS cases and non-ALS controls is critical to understanding these mechanisms. We used Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to characterize the proteomes of the motor cortex from ALS cases (n = 8) and control subjects (n = 8). A total of 1427 proteins were identified at a critical local false discovery rate < 5%; 187 of these exhibited significant expression differences between ALS cases and controls. Of these, 91 proteins were significantly upregulated and 96 proteins were significantly downregulated. Bioinformatics analysis revealed that these proteins are involved in molecular transport, protein trafficking, free radical scavenging, lipid metabolism, cell death and survival, nucleic acid metabolism, inflammatory response or amino acid metabolism and carbohydrate metabolism. Differentially expressed proteins were subjected to pathway analysis. This revealed abnormalities in pathways involving mitochondrial function, sirtuin signaling, oxidative phosphorylation, glycolysis, phagosome maturation, SNARE signaling, redox regulation and several others. Core analysis revealed mitochondrial dysfunction to be the top canonical pathway. The top-enriched networks involved JNK activation and inhibition of AKT signaling, suggesting that disruption of these signaling pathways could lead to demise of motor neurons in the ALS motor cortex.

Mitochondrial genome study in blood of maternally inherited ALS cases

BackgroundALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy.ResultsWe identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients.ConclusionOur results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer’s and Parkinson’s diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.

Elucidating critical origin for capacity fading in High-voltage coin cell with FSI-based electrolyte

F-containing functional electrolytes have been extensively investigated to improve the performance of Li-metal batteries as they generate stable LiF-based solid–electrolyte interphase layers, improving Li deposition/dissolution efficiency. However, these imide-based electrolytes corrode not only the Al current collector but also the stainless steel (SS) component of the coin cell at high operating voltages. Additionally, deciding upon which part of the corrosion has a greater effect on the performance degradation remains a topic of debate. In this study, through systematic cell design exposing SS to LiFSI-based electrolyte, it is found that SS corrosion is a more dominant cause of capacity fading than the Al case. Moreover, the computational study reveals that the electron transfer from Al to SS decomposes FSI– and the resulting byproducts finally corrode Al. To develop stable cells by removing corrosion factors, the SS and Al-free pouch-type cells are proposed by integrating carbon current collectors and locally high-concentration electrolyte and exhibit 430 cycles with a coulombic efficiency of 99.93%. This study demonstrates the importance of careful selection of cell components and systematic cell design to ensure a robust interface at the cathode side, suggesting the necessity to develop a new testing cell to replace the current coin-cell platform.

THE AMYOTROPIC LATERAL SCLEROSIS AND FUNCTIONAL RATING SCALE (ALSFRS)

Research material and methods: During the last five years, 60 patients from different parts of Georgia, including Samegrolo, Kartli, Adjara, Abkhazia, Guria, Kakheti regions have been studied, searched and examined by us. The Georgian Neurologists Corps participated and helped us in finding patients. With the consent of the individual patient, which is confirmed in writing, the study was conducted in accordance with the modern requirements of research. We studied patient's anamnesis, physical data, evaluated their mental, cognitive functions and neurological status. We have also interviewed family members, as it was often difficult for the patient to accurately describe the symptoms. Brain MRI and electromyography were also performed. 60 patients with different forms of ALS participated in the study, including 34 (56.66%) men and 26 (43.33%) women. Their age ranges from 30 to 81 years. Patients were included in the study according to the El Escorial criteria. Among those examined by us, the disease began mainly with muscle numbness, weakness of the limbs, fasciculations, in 36 (60%) patients with speech difficulties. According to our research, the diagnosis of ALS is difficult until muscle atrophy and tremors are detected. There are relatively less cases of ALS (23 (38.33%) patients) with symptoms of one or both legs. At this time, the patients felt uncomfortable while walking, the ankle lost its flexibility, its range of motion was limited. muscle weakness is expressed; muscle spasms; increase of deep reflexes or expansion of the reflexogenic zone; pathological reflexes; pronounced muscle atrophy; increased spasticity; At this time, the upper limbs were less damaged, although the flexibility of the fingers in the upper limbs is limited. ALS with bulbar events was detected in 24 (40%) patients with difficulty speaking, the patient spoke "through the nose", later had difficulty swallowing. Disturbance of speech (dysarthria, anarthria), voice production disorder (dysphonia, aphonia). Disappearance of soft palate and throat reflexes, salivation, breathing disorders were soon added to the symptoms; While in the 11 (18.33%) patients with ALS confirmed by us, the symptoms included signs of both lower and upper motor neuron damage, the upper motor neuron showed: muscle hypertonia, hyperreflexia, pathological Babinski reflex; and in case of damage to the lower motoneurons: muscle weakness and atrophy, involuntary fasciculations. Thus, for the first time in Georgia, we determined the structure and characteristics of the most common syndromes of amyotrophic lateral sclerosis in over the last 5 years, and the prevalence of patients with this disease, taking into account age, sex, disease anamnesis, and other symptoms.