Phenotypic selection patterns in a hybrid zone between two Calceolaria species with contrasting pollinators: insights from field surveys and fitness assessments.

Hybrid zones provide natural experimental settings to test hypotheses about species divergence. We concentrated on a hybrid swarm in which oil-collecting bees and flower-pecking birds act as pollinators of two Calceolaria species. We asked whether both pollinators contributed to flower divergence by differentially promoting prezygotic fitness at the phenotypic extremes that represent parentals. We studied pollinator-mediated selection on phenotypic traits critical in plant-pollinator mechanical interaction, namely plant height, reward-to-stigma distance, and flower shape. We utilised the quantity and quality of pollen deposited as fitness measures and distinguished between the contribution of the two pollinator types. Results showed uni- and bivariate disruptive selection for most traits through pollen grains deposited by both pollinators. Bird-mediated fitness favoured low plants with a long reward-to-stigma distance and a straight corolla, while bee-mediated fitness favoured tall plants with a short reward-to-stigma distance and curved corolla. In addition, stabilising selection at one end of the phenotypic range showed a bird-mediated reproductive asymmetry within the swarm. The disruptive pattern was countered, albeit weakly, by hybrids receiving higher-quality pollen on the stigmas. Results suggest that pollinator-mediated selection promotes divergence of integrated flower phenotypes mechanically adjusted either to bees or birds underscoring the importance of pollinator specialisation in diversification.

Factors associated with the severity of COVID-19 outcomes in people with neuromuscular diseases: Data from the International Neuromuscular COVID-19 Registry.

BACKGROUND AND PURPOSE: Clinical outcome information on patients with neuromuscular diseases (NMDs) who have been infected with SARS-CoV-2 is limited. The aim of this study was to determine factors associated with the severity of COVID-19 outcomes in people with NMDs. METHODS: Cases of NMD, of any age, and confirmed/presumptive COVID-19, submitted to the International Neuromuscular COVID-19 Registry up to 31 December 2021, were included. A mutually exclusive ordinal COVID-19 severity scale was defined as follows: (1) no hospitalization; (2) hospitalization without oxygenation; (3) hospitalization with ventilation/oxygenation; and (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs) for severe outcome, adjusting for age, sex, race/ethnicity, NMD, comorbidities, baseline functional status (modified Rankin scale [mRS]), use of immunosuppressive/immunomodulatory medication, and pandemic calendar period. RESULTS: Of 315 patients from 13 countries (mean age 50.3 [±17.7] years, 154 [48.9%] female), 175 (55.5%) were not hospitalized, 27 (8.6%) were hospitalized without supplemental oxygen, 91 (28.9%) were hospitalized with ventilation/supplemental oxygen, and 22 (7%) died. Higher odds of severe COVID-19 outcomes were observed for: age ≥50 years (50-64 years: OR 2.4, 95% confidence interval [CI] 1.33-4.31; >64 years: OR 4.16, 95% CI 2.12-8.15; both vs. <50 years); non-White race/ethnicity (OR 1.81, 95% CI 1.07-3.06; vs. White); mRS moderately severe/severe disability (OR 3.02, 95% CI 1.6-5.69; vs. no/slight/moderate disability); history of respiratory dysfunction (OR 3.16, 95% CI 1.79-5.58); obesity (OR 2.24, 95% CI 1.18-4.25); ≥3 comorbidities (OR 3.2, 95% CI 1.76-5.83; vs. ≤2; if comorbidity count used instead of specific comorbidities); glucocorticoid treatment (OR 2.33, 95% CI 1.14-4.78); and Guillain-Barré syndrome (OR 3.1, 95% CI 1.35-7.13; vs. mitochondrial disease). CONCLUSIONS: Among people with NMDs, there is a differential risk of COVID-19 outcomes according to demographic and clinical characteristics. These findings could be used to develop tailored management strategies and evidence-based recommendations for NMD patients.

Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. OBJECTIVES: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. METHODS: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. RESULTS: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4. CONCLUSION: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.

Differences between suicide attempts and other psychiatric hospital emergencies.

INTRODUCTION: In Spain, a comparative research study between those patients treated for suicide attempt and others treated by any other reason hasn't been found. The aim of this study is to describe the differences between both types of patients in relation to sociodemographic and clinic variables together with the adverse vital events and the suicidal ideation. METHODOLOGY: A descriptive, multicentric and case-controlled study carried out in psychiatric hospital emergencies where 207 patients had been evaluated for a suicidal attempt (cases) and 233 were also evaluated by any other reasons (checkings). RESULTS: The cases presented a larger percentage of previous suicide attempts (45.4% vs. 30.0%; p=0.001) and a lower rates of prior emergency care (55.6% vs. 65.7%; p=0.030) of a history of mental disorder (77.8% vs. 86.7%; p=0.014) and follow-up in mental health. The 31.8% (n=74) exhibited suicidal ideation at the time of care and the 61.4% (n=143) expressed their desire to die when questioned. CONCLUSIONS: Neither a specific sociodemographic nor clinic profile of those who try to commit suicide has been found. But a high percentage of patients with suicidal ideation were identified in people treated for other reasons. The results emphasize the need to consider and evaluate the ideation of death and the risk of suicide in all the patients treated in psychiatric hospital emergencies.

Amyotrophic lateral sclerosis modifies progenitor neural proliferation in adult classic neurogenic brain niches.

BACKGROUND: Adult neurogenesis persists through life at least in classic neurogenic niches. Neurogenesis has been previously described as reduced in neurodegenerative diseases. There is not much knowledge about is adult neurogenesis is or not modified in amyotrophy lateral sclerosis (ALS). All previous publications has studied the ALS SOD1 (superoxide dismutase) transgenic mouse model. The purpose of this study is to examine the process of adult neurogenesis in classic niches (subventricular zone [SVZ] and subgranular zone [SGZ] of the dentate gyrus) in patients with amyotrophic lateral sclerosis (ALS), both with (ALS-FTD) and without associated frontotemporal dementia (FTD). METHODS: We studied 9 autopsies of patients with ALS (including 2 with ALS-FTD) and 4 controls. ALS was confirmed histologically. Studies of the SVZ and SGZ were conducted using markers of proliferation (Ki-67, PCNA), of pluripotent neural progenitor cells (GFAPδ), neuroblasts (PSA-NCAM, DCX, TUJ1), and an astrocyte marker (GFAP). Results were analyzed with non-parametric tests. We then studied correlations between the different markers and the percentage of phosphorylated TDP-43 (pTDP-43). RESULTS: We observed a statistically significant increase in proliferation in the SVZ in all patients with ALS. While this increase was more marked in ALS forms associated with dementia, the small sample size does not permit a statistical subgroup analysis. In contrast, proliferation in the SGZ was decreased in all patients. These alterations showed a positive and direct correlation with the percentage of pTDP-43 in the SVZ, and a negative, exponential correlation with that percentage in the SGZ. CONCLUSIONS: We observed alterations of the proliferation of neural progenitor in classic adult neurogenic niches in patients with ALS. The 2 neurogenic niches exhibited opposite changes such that proliferation increased in the SVZ and decreased in the SGZ.

Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP.

PURPOSE OF REVIEW: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a highly disabling, life-threatening disease characterized by progressive sensorimotor and autonomic neuropathy. The profile of the disease across Europe is inadequately understood at present. RECENT FINDINGS: The incidence and clinical presentation of TTR-FAP varies widely within Europe, with early and late-onset disease subtypes. In those regions in which the disease is endemic (Portugal, Sweden, Cyprus, and Majorca), a Val30Met substitution in the TTR gene is the predominant genetic cause, whereas in the rest of Europe, cases of TTR-FAP are mainly sporadic with genetic heterogeneity. Current management strategies lack cohesion and patients can experience years of misdiagnosis and suboptimal treatment. SUMMARY: The article aims to disseminate the findings and recommendations from two recent meetings of the European Network for TTR-FAP (ATTReuNET), a panel comprising representatives from 10 European countries (Bulgaria, Cyprus, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and Turkey) with expertise in the diagnosis and management of TTR-FAP. We explore the epidemiology and genetic mark of TTR-FAP across Europe and assess current management strategies, with a view to developing an alternative framework - a networked approach to disease management with an emphasis on collaboration and sharing of best practice.

Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis.

PURPOSE: We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS). METHODS: This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with (18)F-fluorodeoxyglucose (FDG), and amyloid-PET with (18)F-florbetaben. RESULTS: Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased (18)F-florbetaben uptake compared to controls. CONCLUSIONS: We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint.

The neuroprotection exerted by memantine, minocycline and lithium, against neurotoxicity of CSF from patients with amyotrophic lateral sclerosis, is antagonized by riluzole.

In a recent study we found that cerebrospinal fluids (CSFs) from amyotrophic lateral sclerosis (ALS) patients caused 20-30% loss of cell viability in primary cultures of rat embryo motor cortex neurons. We also found that the antioxidant resveratrol protected against such damaging effects and that, surprisingly, riluzole antagonized its protecting effects. Here we have extended this study to the interactions of riluzole with 3 other recognized neuroprotective agents, namely memantine, minocycline and lithium. We found: (1) by itself riluzole exerted neurotoxic effects at concentrations of 3-30 µM; this cell damage was similar to that elicited by 30 µM glutamate and a 10% dilution of ALS/CSF; (2) memantine (0.1-30 µM), minocycline (0.03-1 µM) and lithium (1-80 µg/ml) afforded 10-30% protection against ALS/CSF-elicited neurotoxicity, and (3) at 1-10 µM, riluzole antagonized the protection afforded by the 3 agents. These results strongly support the view that at the riluzole concentrations reached in the brain of patients, the neurotoxic effects of this drug could be masking the potential neuroprotective actions of new compounds being tested in clinical trials. Therefore, in the light of the present results, the inclusion of a group of patients free of riluzole treatment may be mandatory in future clinical trials performed in ALS patients with novel neuroprotective compounds.

Effect of Intravitreal Anti-Endothelial Growth Factor Agents on Renal Function in Patients With Diabetes Mellitus.

Introduction: Intravitreal administration of vascular endothelial growth factor inhibitors (anti-VEGF) is the treatment of choice in retinal pathology associated with type 2 diabetes mellitus (DM2). We aimed to analyze the effect of intravitreal anti-VEGF administration on renal function in patients with DM2. Methods: This is a single-center retrospective and observational study of patients with DM2 with and without chronic kidney disease (CKD). We analyzed the evolution of renal function after anti-VEGF onset, compared with a control group. Results: We included 45 patients (55.6% male) who received anti-VEGF therapy. Mean age was 74.4±11.5 (50-91) years. These were compared with 45 patients with similar characteristics. After 12 months, 76.3% had CKD with a mean reduction in estimated glomerular filtration rate (eGFR) of 19.4%. Nine patients (20%) had a >25% reduction in eGFR, and 3 patients (6.7%) had a >50% reduction in GFR. At 24 months, 80% of patients had CKD with a mean eGFR decrease of 28%. The mean eGFR slope of patients who had received anti-VEGF treatment was 10 ml/min/year compared to 1.5 ml/min/year in the control group (P < 0.05). After the first administration, 5 patients (17.2%) in the CKD group required renal replacement therapy during follow-up (mean time 22±12 months). Main risk factors for need of dialysis were age, presence of previous CKD, and baseline proteinuria. Conclusion: Intravitreal anti-VEGF administration is a risk factor for CKD and rapid progression to end-stage kidney disease in patients with previous CKD. Knowing these drugs' implications is crucial to avoid CKD progression and opportunely limit their use in certain patients.

Analysis of the C9orf72 gene in patients with amyotrophic lateral sclerosis in Spain and different populations worldwide.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.

Phenotype and clinical outcomes of Glu89Lys hereditary transthyretin amyloidosis: a new endemic variant in Spain.

BACKGROUND: The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain. METHODS: Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals. RESULTS: Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7-9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis (p < 0.001). Haplotype analysis revealed a common origin from an ancestor who lived ∼500 years ago in southeast Spain. CONCLUSIONS: Glu89Lys ATTRv is a TTR variant with a founder effect in Spain. It is associated with near complete penetrance, early onset and mixed cardiac and neurologic phenotype. Patients have poor prognosis, particularly if not treated with disease-modifying therapies.

Effect of Immunosuppressive Treatments on Kidney Outcomes After Gross Hematuria-Related Acute Kidney Injury in Older Patients With IgA Nephropathy.

Introduction: Macroscopic hematuria (MH) bouts, frequently accompanied by acute kidney injury (AKI-MH) are one of the most common presentations of IgA nephropathy (IgAN) in the elderly. Immunosuppressive therapies are used in clinical practice; however, no studies have analyzed their efficacy on kidney outcomes. Methods: This is a retrospective, multicenter study of a cohort of patients aged ≥50 years with biopsy-proven IgAN presenting with AKI-MH. Outcomes were complete, partial, or no recovery of kidney function at 1 year after AKI-MH, and kidney survival at 1, 2, and 5 years. Propensity score matching (PSM) analysis was applied to balance baseline differences between patients treated with immunosuppression and those not treated with immunosuppression. Results: The study group consisted of 91 patients with a mean age of 65 ± 15 years, with a mean follow-up of 59 ± 36 months. Intratubular red blood cell (RBC) casts and acute tubular necrosis were found in all kidney biopsies. The frequency of endocapillary hypercellularity and crescents were low. Immunosuppressive therapies (corticosteroids alone or combined with mycophenolate mofetil or cyclophosphamide) were prescribed in 52 (57%) patients, whereas 39 (43%) received conservative treatment. There were no significant differences in the proportion of patients with complete, partial, or no recovery of kidney function at 1 year between patients treated with immunosuppression and those not treated with immunosuppression (29% vs. 36%, 30.8% vs. 20.5% and 40.4 % vs. 43.6%, respectively). Kidney survival at 1, 3, and 5 years was similar among treated and untreated patients (85% vs. 81%, 77% vs. 76% and 72% vs. 66%, respectively). Despite the PSM analysis, no significant differences were observed in kidney survival between the two groups. Fourteen patients (27%) treated with immunosuppression had serious adverse events. Conclusions: Immunosuppressive treatments do not modify the unfavorable prognosis of patients with IgAN who are aged ≥50 years presenting with AKI-MH, and are frequently associated with severe complications.

Anything New in the Treatment of Obesity in Obese Patients with CKD?

Treatment for obesity in patients with CKD englobes a wide range of options, from lifestyle modification to bariatric surgery. Weight loss improves metabolic parameters and stimulates changes in renal function that lead to improvement of glomerular hyperfiltration. The most common clinical presentation is a slowly increasing non-nephrotic proteinuria that is followed by a progressive decline of kidney function. The use of multitarget therapies, with appropriate dietary education, emerging diets, the use of new RAAS blocking agents, the combination of iSGLT2 or GLP-1 agonists, as well as bariatric surgery, may play a key role in finally achieving the desired nephroprotection in this CKD population. New therapeutic agents and novel biomarkers, such as adipocyte cytokines, are needed to monitor and mitigate progression to end-stage renal disease. The emerging "lipidomics" and the role of nonalcoholic fatty liver are relevant research lines.

Estimating the annual economic burden for the management of patients with transthyretin amyloid polyneuropathy in Spain.

Background: Transthyretin amyloid polyneuropathy (ATTR-PN) is a fatal disease associated with substantial burden of illness. Three therapies are approved by the European Medicines Agency for the management of this rare disease. The aim of this study was to compare the total annual treatment specific cost per-patient associated with ATTR-PN in Spain.Methods: An Excel-based patient burden and cost estimator tool was developed to itemize direct and indirect costs related to treatment with inotersen, patisiran, and tafamidis in the context of ATTR-PN. The product labels and feedback from five Spanish ATTR-PN experts were used to inform resource use and cost inputs.Results: Marked differences in costs were observed between the three therapies. The need for patisiran- and inotersen-treated patients to visit hospitals for pre-treatment, administration, and monitoring was associated with increased patient burden and costs compared to those treated with tafamidis. Drug acquisition costs per-patient per-year were 291,076€ (inotersen), 427,250€ (patisiran) and 129,737€ (tafamidis) and accounted for the majority of total costs. Overall, the total annual per-patient costs were lowest for patients treated with tafamidis (137,954€), followed by inotersen (308,358€), and patisiran (458,771€).Conclusions: Treating patients with tafamidis leads to substantially lower costs and patient burden than with inotersen or patisiran.

Clinical and therapeutic features of myasthenia gravis in adults based on age at onset.

OBJECTIVE: To describe the characteristics of patients with very-late-onset myasthenia gravis (MG). METHODS: This observational cross-sectional multicenter study was based on information in the neurologist-driven Spanish Registry of Neuromuscular Diseases (NMD-ES). All patients were >18 years of age at onset of MG and onset occurred between 2000 and 2016 in all cases. Patients were classified into 3 age subgroups: early-onset MG (age at onset <50 years), late-onset MG (onset ≥50 and <65 years), and very-late-onset MG (onset ≥65 years). Demographic, immunologic, clinical, and therapeutic data were reviewed. RESULTS: A total of 939 patients from 15 hospitals were included: 288 (30.7%) had early-onset MG, 227 (24.2%) late-onset MG, and 424 (45.2%) very-late-onset MG. The mean follow-up was 9.1 years (SD 4.3). Patients with late onset and very late onset were more frequently men (p < 0.0001). Compared to the early-onset and late-onset groups, in the very-late-onset group, the presence of anti-acetylcholine receptor (anti-AChR) antibodies (p < 0.0001) was higher and fewer patients had thymoma (p < 0.0001). Late-onset MG and very-late-onset MG groups more frequently had ocular MG, both at onset (<0.0001) and at maximal worsening (p = 0.001). Although the very-late-onset group presented more life-threatening events (Myasthenia Gravis Foundation of America IVB and V) at onset (p = 0.002), they required fewer drugs (p < 0.0001) and were less frequently drug-refractory (p < 0.0001). CONCLUSIONS: Patients with MG are primarily ≥65 years of age with anti-AChR antibodies and no thymoma. Although patients with very-late-onset MG may present life-threatening events at onset, they achieve a good outcome with fewer immunosuppressants when diagnosed and treated properly.

Assessment of patients with hereditary transthyretin amyloidosis - understanding the impact of management and disease progression.

Timely diagnosis of hereditary variant transthyretin (ATTRv) amyloidosis is critical for appropriate treatment and optimal outcomes. Significant differences are seen between patients receiving treatment and those who are not, though disease progression may continue despite treatment in some patients. Healthcare professionals caring for patients with ATTRv amyloidosis therefore need reliable ongoing assessments to understand the continuing course of disease and make appropriate treatment choices on an individual basis. Various signs and symptoms experienced by patients may be evaluated as indicators of disease progression, though there is currently no validated score that can be used for such ongoing assessment. Recognizing this situation, a group of clinicians highly experienced in ATTR amyloidosis developed an approach to understand and define disease progression in diagnosed and treated patients with ATTRv amyloidosis. The suggested approach is based on the recognition of distinct phenotypes which may usefully inform the particular tools, tests and investigations that are most likely to be appropriate for individual patients. It is aimed at implementing appropriate and ongoing assessment of patients being treated for ATTRv amyloidosis, such that the effectiveness of management can be usefully assessed throughout the course of disease and management can be tailored according to the patient's requirements.

Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations.

Diagnosis in the early stages of hereditary transthyretin (ATTR) amyloidosis is imperative to support timely treatment to prevent or delay disease progression. Genetic testing in the setting of genetic counselling enables identification of carriers of a TTR gene mutation who are therefore at risk of developing TTR-associated disease. Knowledge of different genotypes and how they manifest in symptomatic disease should facilitate development of a structured and targeted approach to enable diagnosis of symptomatic disease in ATTR amyloidosis mutation carriers on the first manifestation of the earliest detectable sign or symptom. A group of experts from across Europe, Israel and Japan met to reach a consensus on such an approach. The proposed approach involves establishing a baseline for key clinical parameters, determination of the timing and frequency of follow-up in TTR mutation carriers based on a predicted age of disease onset, and recognition of the likely initial clinical signs and symptoms aligned with the phenotype of the specific TTR gene mutation and family history. Minimum criteria for diagnosis of symptomatic disease have been agreed, which it is hoped will ensure diagnosis of ATTR amyloidosis at the earliest possible stage in people with a known TTR mutation.

Notch Signalling in the Hippocampus of Patients With Motor Neuron Disease.

INTRODUCTION: The Notch signalling pathway regulates neuronal survival. It has some similarities with the APP signalling pathway, and competes with the latter for α- and γ-secretase proteolytic complexes. The objective of this study was to study the Notch signalling pathway in the hippocampi of patients with motor neuron disease. METHODS: We studied biological material from the autopsies of 12 patients with motor neuron disease and 4 controls. We analysed the molecular markers of the Notch and APP signalling pathways, TDP43, tau, and markers of neurogenesis. RESULTS AND CONCLUSION: Low NICD expression suggests Notch signalling pathway inactivation in neurons. Inactivation of the pathway despite increased Notch1 expression is associated with a lack of α-secretase expression. We observed increased ß-secretase expression associated with activation of the amyloid cascade of APP, leading to increases in amyloid-ß and AICD peptides and decreased levels of Fe65. Inactivation of the Notch signalling pathway is an important factor in decreased neurogenic response in the hippocampi of patients with amyotrophic lateral sclerosis.

Inhibition impairment in frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease: clinical assessment and metabolic correlates.

The ability to reject an automatic tendency, i.e. inhibition, has been linked to the prefrontal cortex, but its neural underpinnings are still controversial. Neurodegenerative diseases represent an interesting model to explore this issue, given its frequent impairment in these disorders. We investigated the inhibitory impairment and its neural basis using four different tests, which evaluate the presence of inhibitory dysfunction (Stroop test, Hayling test, and two graphical perseveration tests), and assessed their correlation with brain metabolism using 18F-fluorodeoxyglucose positron emission tomography in a group of 76 participants with behavioral variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and healthy controls (HC). Inhibition impairment was more frequent in bvFTD and AD, than ALS and HC. AD and bvFTD only differed in the strategy used in Hayling test, and the frequency of impairment in graphical perseveration tests. Correlation between inhibition tests was moderate. The Stroop test correlated with several regions of the frontal and parietal lobes, mainly on the left side. Hayling test correlated with almost all regions of the frontal lobe and, especially, with the orbitofrontal cortex. Some differences in the impaired regions in each disease were found. Inhibition ability was mainly impaired in bvFTD and AD, and it correlated with the bilateral frontal lobe metabolism. There were certain particularities according to the specific task and patients evaluated. These dissimilarities may support the concept of inhibition as a multidimensional construct, with the involvement of common and divergent neural mechanisms.

Collagen XIX Alpha 1 Improves Prognosis in Amyotrophic Lateral Sclerosis.

The identification of more reliable diagnostic or prognostic biomarkers in age-related neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), is urgently needed. The objective in this study was to identify more reliable prognostic biomarkers of ALS mirroring neurodegeneration that could be of help in clinical trials. A total of 268 participants from three cohorts were included in this study. The muscle and blood cohorts were analyzed in two cross-sectional studies, while the serial blood cohort was analyzed in a longitudinal study at 6-monthly intervals. Fifteen target genes and fourteen proteins involved in muscle physiology and differentiation, metabolic processes and neuromuscular junction dismantlement were studied in the three cohorts. In the muscle biopsy cohort, the risk for a higher mortality in an ALS patient that showed high Collagen type XIX, alpha 1 (COL19A1) protein levels and a fast progression of the disease was 70.5% (P < 0.05), while in the blood cohort, this risk was 20% (P < 0.01). In the serial blood cohort, the linear mixed model analysis showed a significant association between increasing COL19A1 gene levels along disease progression and a faster progression during the follow-up period of 24 months (P < 0.05). Additionally, higher COL19A1 levels and a faster progression increased 17.9% the mortality risk (P < 0.01). We provide new evidence that COL19A1 can be considered a prognostic biomarker that could help the selection of homogeneous groups of patients for upcoming clinical trial and may be pointed out as a promising therapeutic target in ALS.