SPECT/CT SUV-based metrics: A promising diagnostic tool in classifying patients with suspected transthyretin cardiac amyloidosis among the different Perugini grades?

OBJECTIVE: The purpose of this study was to evaluate the contribution of single photon emission computed tomography/computed tomography (SPECT/CT) standardized uptake value (SUV) metrics in classifying patients with suspected transthyretin cardiac amyloidosis (ATTR-CA) among the different Perugini grades. SUBJECTS AND METHODS: One hundred four patients suspected of ATTR-CA underwent planar scintigraphy with bone seeking tracer (99mTc pyrophosphate-PYP). Patients were classified according to the Perugini scale, the H/CL, H/Bone and H/Bkg ratios. A subset of 48 patients received additional SPECT/CT. Single photon emission computed tomography/CT SUV quantitative parameters, of the heart, myocardium, lungs, liver, soft tissues, bone, and SUV ratios (SUVmaxmyo, SUVmaxlungs, SUVmaxliver, SUVmaxbone and SUVmaxsoft tissue ratios), were evaluated in order to investigate potential metrics that could more clearly differentiate Perugini grades. RESULTS: A total of 33.7% of patients were considered grade 0, 34.6% grade 1 and 31.7% grade 2/3. A combination of H/CL >1.33 and H/Bone >0.85 showed the highest sensitivity 100%. Standardized uptake value-based metrics clearly differentiated grade 0 or 1 vs grades 2 or 3, whereas no significant difference was found between grades 0 and 1, or between grades 1 and 2. The combined cut-off values H/CL 1.33 and SUVmaxmyo 2.88 yielded 100% sensitivity and 84.6% specificity in differentiating ATTR-CA positives vs negatives. The metric SUVmaxmyo/SUVmaxliver was the best metric to classify patients with grade 1 as negative (grade 0) or positive (grade 2 or 3). CONCLUSION: Single photon emission computed tomography/CT SUV metrics could be complementary to planar scintigraphy in classifying patients among the different Perugini grades. The ratio SUVmaxmyo/SUVmaxliver was the only parameter with high affinity to differentiate patients with grade 1, as grade 0 or grade 2/3 for ATTR-CA.

Long-term associations between objective sleep quality and quantity and verbal memory performance in normal cognition and mild cognitive impairment.

Introduction: Although the link between sleep and memory function is well established, associations between sleep macrostructure and memory function in normal cognition and Mild Cognitive Impairment remain unclear. We aimed to investigate the longitudinal associations of baseline objectively assessed sleep quality and duration, as well as time in bed, with verbal memory capacity over a 7-9 year period. Participants are a well-characterized subsample of 148 persons (mean age at baseline: 72.8 ± 6.7 years) from the Cretan Aging Cohort. Based on comprehensive neuropsychiatric and neuropsychological evaluation at baseline, participants were diagnosed with Mild Cognitive Impairment (MCI; n = 79) or found to be cognitively unimpaired (CNI; n = 69). Sleep quality/quantity was estimated from a 3-day consecutive actigraphy recording, whereas verbal memory capacity was examined using the Rey Auditory Verbal Learning Test (RAVLT) and the Greek Passage Memory Test at baseline and follow-up. Panel models were applied to the data using AMOS including several sociodemographic and clinical covariates. Results: Sleep efficiency at baseline directly predicted subsequent memory performance in the total group (immediate passage recall: ß = 0.266, p = 0.001; immediate word list recall: ß = 0.172, p = 0.01; delayed passage retrieval: ß = 0.214, p = 0.002) with the effects in Passage Memory reaching significance in both clinical groups. Wake after sleep onset time directly predicted follow-up immediate passage recall in the total sample (ß = -0.211, p = 0.001) and in the MCI group (ß = -0.235, p = 0.02). In the total sample, longer 24-h sleep duration was associated with reduced memory performance indirectly through increased sleep duration at follow-up (immediate passage recall: ß = -0.045, p = 0.01; passage retention index: ß = -0.051, p = 0.01; RAVLT-delayed recall: ß = -0.048, p = 0.009; RAVLT-retention index:ß = -0.066, p = 0.004). Similar indirect effects were found for baseline 24-h time in bed. Indirect effects of sleep duration/time in bed were found predominantly in the MCI group. Discussion: Findings corroborate and expand previous work suggesting that poor sleep quality and long sleep duration predict worse memory function in elderly. Timely interventions to improve sleep could help prevent or delay age-related memory decline among non-demented elderly.

IL-6 Enhances the Negative Impact of Cortisol on Cognition among Community-Dwelling Older People without Dementia.

There is growing evidence that high basal cortisol levels and systemic inflammation independently contribute to cognitive decline among older people without dementia. The present cross-sectional study examined (a) the potential synergistic effect of cortisol levels and systemic inflammation on executive function and (b) whether this effect is more prominent among older people with mild cognitive impairment (MCI). A sub-sample of 99 patients with MCI and 84 older people without cognitive impairment (CNI) (aged 73.8 ± 7.0 years) were recruited from a large population-based cohort in Crete, Greece, and underwent comprehensive neuropsychiatric and neuropsychological evaluation and a single morning measurement of cortisol and IL-6 plasma levels. Using moderated regression models, we found that the relation between cortisol and executive function in the total sample was moderated by IL-6 levels (b = -0.994, p = 0.044) and diagnostic group separately (b = -0.632, p < 0.001). Moreover, the interaction between cortisol and IL-6 levels was significant only among persons with MCI (b = -0.562, p < 0.001). The synergistic effect of stress hormones and systemic inflammation on cognitive status appears to be stronger among older people who already display signs of cognitive decline. Targeting hypercortisolemia and inflammation may be a promising strategy toward improving the course of cognitive decline.

Personalized screening and risk profiles for Mild Cognitive Impairment via a Machine Learning Framework: Implications for general practice.

OBJECTIVES: Diagnosis of Mild Cognitive Impairment (MCI) requires lengthy diagnostic procedures, typically available at tertiary Health Care Centers (HCC). This prospective study evaluated a flexible Machine Learning (ML) framework toward identifying persons with MCI or dementia based on information that can be readily available in a primary HC setting. METHODS: Demographic and clinical data, informant ratings of recent behavioral changes, self-reported anxiety and depression symptoms, subjective cognitive complaints, and Mini Mental State Examination (MMSE) scores were pooled from two aging cohorts from the island of Crete, Greece (N = 763 aged 60-93 years) comprising persons diagnosed with MCI (n = 277) or dementia (n = 153), and cognitively non-impaired persons (CNI, n = 333). A Balanced Random Forest Classifier was used for classification and variable importance-based feature selection in nested cross-validation schemes (CNI vs MCI, CNI vs Dementia, MCI vs Dementia). Global-level model-agnostic analyses identified predictors displaying nonlinear behavior. Local level agnostic analyses pinpointed key predictor variables for a given classification result after statistically controlling for all other predictors in the model. RESULTS: Classification of MCI vs CNI was achieved with improved sensitivity (74 %) and comparable specificity (73 %) compared to MMSE alone (37.2 % and 94.3 %, respectively). Additional high-ranking features included age, education, behavioral changes, multicomorbidity and polypharmacy. Higher classification accuracy was achieved for MCI vs Dementia (sensitivity/specificity = 87 %) and CNI vs Dementia (sensitivity/specificity = 94 %) using the same set of variables. Model agnostic analyses revealed notable individual variability in the contribution of specific variables toward a given classification result. CONCLUSIONS: Improved capacity to identify elderly with MCI can be achieved by combining demographic and medical information readily available at the PHC setting with MMSE scores, and informant ratings of behavioral changes. Explainability at the patient level may help clinicians identify specific predictor variables and patient scores to a given prediction outcome toward personalized risk assessment.

Study of Alzheimer's disease- and frontotemporal dementia-associated genes in the Cretan Aging Cohort.

Using exome sequencing, we analyzed 196 participants of the Cretan Aging Cohort (CAC; 95 with Alzheimer's disease [AD], 20 with mild cognitive impairment [MCI], and 81 cognitively normal controls). The APOE ε4 allele was more common in AD patients (23.2%) than in controls (7.4%; p < 0.01) and the PSEN2 p.Arg29His and p.Cys391Arg variants were found in 3 AD and 1 MCI patient, respectively. Also, we found the frontotemporal dementia (FTD)-associated TARDBP gene p.Ile383Val variant in 2 elderly patients diagnosed with AD and in 2 patients, non CAC members, with the amyotrophic lateral sclerosis/FTD phenotype. Furthermore, the p.Ser498Ala variant in the positively selected GLUD2 gene was less frequent in AD patients (2.11%) than in controls (16%; p < 0.01), suggesting a possible protective effect. While the same trend was found in another local replication cohort (n = 406) and in section of the ADNI cohort (n = 808), this finding did not reach statistical significance and therefore it should be considered preliminary. Our results attest to the value of genetic testing to study aged adults with AD phenotype.

Structural Evolution of Primate Glutamate Dehydrogenase 2 as Revealed by In Silico Predictions and Experimentally Determined Structures.

Glutamate dehydrogenase (GDH) interconverts glutamate to a-ketoglutarate and ammonia, interconnecting amino acid and carbohydrate metabolism. In humans, two functional GDH genes, GLUD1 and GLUD2, encode for hGDH1 and hGDH2, respectively. GLUD2 evolved from retrotransposition of the GLUD1 gene in the common ancestor of modern apes. These two isoenzymes are involved in the pathophysiology of human metabolic, neoplastic, and neurodegenerative disorders. The 3D structures of hGDH1 and hGDH2 have been experimentally determined; however, no information is available about the path of GDH2 structure changes during primate evolution. Here, we compare the structures predicted by the AlphaFold Colab method for the GDH2 enzyme of modern apes and their extinct primate ancestors. Also, we analyze the individual effect of amino acid substitutions emerging during primate evolution. Our most important finding is that the predicted structure of GDH2 in the common ancestor of apes was the steppingstone for the structural evolution of primate GDH2s. Two changes with a strong functional impact occurring at the first evolutionary step, Arg443Ser and Gly456Ala, had a destabilizing and stabilizing effect, respectively, making this step the most important one. Subsequently, GDH2 underwent additional modifications that fine-tuned its enzymatic properties to adapt to the functional needs of modern-day primate tissues.

High Hereditary Transthyretin-Related Amyloidosis Prevalence in Crete: Genetic Heterogeneity and Distinct Phenotypes.

Background and Objectives: Our goal was to study hereditary transthyretin-related amyloidosis (hATTR) in Crete, Greece. Methods: We aimed at ascertaining all hATTR cases in Crete, an island of 0.62 million people. For this, we evaluated patients with polyneuropathy, autonomic involvement, cardiomyopathy, and/or ophthalmopathy suggestive of hATTR, who presented to the physicians of this study or were referred to them by other physicians. Genetic analyses were performed on all patients suspected of suffering from hATTR. We included in our observational longitudinal cohort study all individuals, residents of Crete, who, during the study period (1993-2019), were found to carry a pathogenic TTR variant. Results: Over the past 27 years, 30 individuals (15 female patients, 15 male patients), from 12 apparently unrelated families, were diagnosed with hATTR, whereas evaluation of their offspring identified 5 asymptomatic TTR pathogenic variant carriers. The most prevalent TTR variant detected was p.Val50Met, affecting 19 patients (11 female patients, 8 male patients) and causing a rather consistent phenotype characterized by predominant polyneuropathy of early adult onset (median age of symptom onset: 30 years; range: 18-37 years). Specifically, patients affected by the p.Val50Met TTR variant experienced progressive sensorimotor disturbances, involving mainly the lower extremities, associated with autonomic and/or gastrointestinal dysfunction. The second most frequent TTR variant was p.Val114Ala, found in 10 patients (4 female patients, 6 male patients) who were affected at an older age (median age of symptom onset: 70 years; range: 54-78 years). This variant caused a predominantly cardiomyopathic phenotype, manifested by congestive heart failure and associated with peripheral neuropathy, carpal tunnel syndrome, and/or autonomic involvement. In these patients, cardiac amyloid deposition was detected on 99m-technetium pyrophosphate scintigraphy and/or heart biopsy. The third TTR variant (p.Arg54Gly) was found in a 50-year-old male patient with ophthalmopathy due to vitreous opacities and positive family history for visual loss. As 22 patients were alive at the end of the study, we calculated the hATTR prevalence in Crete to be 35 cases per 1 million inhabitants. Discussion: Our study revealed that the prevalence of hATTR in Crete is one of the world's highest. Three different pathogenic TTR variants causing distinct clinical phenotypes were identified in this relatively small population pool.

The p.Pro482Ala Variant in the CNNM2 Gene Causes Severe Hypomagnesemia Amenable to Treatment with Spironolactone.

Renal hypomagnesemia syndromes involving CNNM2 protein pathogenic variants are associated with variable degrees of neurocognitive dysfunction and hypomagnesemia. Here, we report a family with a novel CNNM2 p.Pro482Ala variant, presenting with overt hypomagnesemia and mild neurological involvement (autosomal dominant renal hypomagnesemia 6, HOMG6, MIM# 613882). Using a bioinformatics approach, we showed that the p.Pro482Ala amino acid substitution causes a 3D conformational change in CNNM2 structure in the cystathionin beta synthase (CBS) domain and the carboxy-terminal protein segment. A novel finding was that aldosterone inhibition with spironolactone helped to alleviate hypomagnesemia and symptoms in the proband.

Interactions of Mediterranean Diet, Obesity, Polypharmacy, Depression and Systemic Inflammation with Frailty Status.

Objective:Comprehensive characterization of potential frailty determinants, including sociodemographic, clinical, dietary, psychological, cognitive and systemic inflammation parameters. Methods:A rural cohort of 186 subjects aged 60-89 years recruited from a community-based study in Crete, Greece (the Cretan Aging Cohort). Frailty was assessed with the Simple "Frail" Questionnaire Screening Tool. Results:Univariate analyses revealed significant (a) positive associations (p<0.01) between frailty and age, widowhood, Geriatric Depression Scale (GDS) score, waist circumference, polypharmacy, IL-6 and (b) negative associations between frailty and frequency of contact with friends, Mini Mental State Examination (MMSE), and adherence to the Mediterranean diet. Multivariate analyses revealed a significant independent contribution of the following variables to frailty: age (B=0.035, p<0.001), GDS score (B=0.041, p=0.034), polypharmacy (B=0.568, p<0.001), waist circumference (B=0.015, p=0,006), plasma IL-6 levels (B=0.189, p=0.004), and adherence to the Mediterranean diet (B=-0.036, p=0.015). Conclusion:Older age, depression symptoms, polypharmacy, waist circumference, poor adherence to Mediterranean diet and IL-6 plasma levels are associated with increased frailty.

Dent-2 disease with a Bartter-like phenotype caused by the Asp631Glu mutation in the OCRL gene.

BACKGROUND: Dent disease is an X-linked disorder characterized by low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and chronic kidney disease (CKD). It is caused by mutations in the chloride voltage-gated channel 5 (CLCN5) gene (Dent disease-1), or in the OCRL gene (Dent disease-2). It is associated with chronic metabolic acidosis; however metabolic alkalosis has rarely been reported. CASE PRESENTATION: We present a family with Dent-2 disease and a Bartter-like phenotype. The main clinical problems observed in the proband included a) primary phosphaturia leading to osteomalacia and stunted growth; b) elevated serum calcitriol levels, leading to hypercalcemia, hypercalciuria, nephrolithiasis and nephrocalcinosis; c) severe salt wasting causing hypotension, hyperaldosteronism, hypokalemia and metabolic alkalosis; d) partial nephrogenic diabetes insipidus attributed to hypercalcemia, hypokalemia and nephrocalcinosis; e) albuminuria, LMWP. Phosphorous repletion resulted in abrupt cessation of hypercalciuria and significant improvement of hypophosphatemia, physical stamina and bone histology. Years later, he presented progressive CKD with nephrotic range proteinuria attributed to focal segmental glomerulosclerosis (FSGS). Targeted genetic analysis for several phosphaturic diseases was unsuccessful. Whole Exome Sequencing (WES) revealed a c.1893C > A variant (Asp631Glu) in the OCRL gene which was co-segregated with the disease in male family members. CONCLUSIONS: We present the clinical characteristics of the Asp631Glu mutation in the OCRL gene, presenting as Dent-2 disease with Bartter-like features. Phosphorous repletion resulted in significant improvement of all clinical features except for progressive CKD. Angiotensin blockade improved proteinuria and stabilized kidney function for several years.

Consensus statement on enzyme replacement therapy for mucopolysaccharidosis IVA in Central and South-Eastern European countries.

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA), or Morquio A syndrome, is a rare inherited metabolic disorder caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. A progressive systemic skeletal chondrodysplasia, leading to significant morbidity and reduced life expectancy is the main clinical feature of this multisystemic disease. Although enzyme replacement therapy with elosulfase alfa is established in Europe, the rarity of disease and other factors still set hurdles in having patients treated in some countries. Aim of this statement is to provide evidence-based guidance for the enzyme replacement treatment of Morquio A patients, harmonizing recommendations from published guidelines with the real-life clinical practice in the Central and South-Eastern European region. PARTICIPANTS: The Consensus Group, convened by 8 Steering Committee (SC) members from 7 Central and South-Eastern European countries, consisted of a multidisciplinary group of 17 experts in the management of MPS in Central and South-Eastern Europe. CONSENSUS PROCESS: The SC met in a first virtual meeting with an external scientific coordinator, to discuss on clinical issues to be analyzed in guidance statements. Statements were developed by the scientific coordinator, evaluated by the SC members in a first modified-Delphi voting and adapted accordingly, to be submitted to the widest audience in the Consensus Conference. Following discussion and further modifications, all participants contributed to a second round of modified-Delphi voting. RESULTS: Nine of ten statements, concerning general guidelines for management of MPS IVA patients and specific recommendations for treatment, received final consensus. CONCLUSIONS: European guidelines and evidence-based recommendations for Morquio A patients should be considered in the real life of Central and South-Eastern European countries and adapted to unique clinical practice approaches and criteria for patients' access to treatment and reimbursement in the region.

Basal Cortisol Levels Are Increased in Patients with Mild Cognitive Impairment: Role of Insomnia and Short Sleep Duration.

BACKGROUND: Mild cognitive impairment (MCI) is frequent in elderly and a risk factor for dementia. Both insomnia and increased cortisol levels are risk factors for MCI. OBJECTIVE: We examined cross-sectionally whether increased cortisol levels are associated with short sleep duration (SSD) and/or the insomnia short sleep duration (ISS) phenotype, in elderly with MCI. METHODS: One hundred twenty-four participants with MCI and 84 cognitively non-impaired controls (CNI)≥60 years underwent medical history, physical examination, neuropsychiatric evaluation, neuropsychological testing, 3-day actigraphy, assessment of subjective insomnia symptoms, and a single morning plasma cortisol level. The short sleep phenotypes were defined by sleep efficiency below the median of the entire sample (i.e.,≤81%) with at least one insomnia symptom (ISS) or without (SSD). ANOVA models were used to compare the various sleep phenotypes to those who did not present either short sleep or insomnia symptoms [non-insomnia (NI)]. RESULTS: MCI participants had higher cortisol levels compared to the CNI group (p = 0.009). MCI participants with insomnia (n = 44) or SSD (n = 38) had higher cortisol levels compared to the NI group (n = 42; p = 0.014 and p = 0.045, respectively). Furthermore, MCI participants with ISS phenotype but not those with insomnia with normal sleep duration had higher cortisol levels compared to NI (p = 0.011 and p = 0.4, respectively). Both linear trend analyses showed that cortisol reached the highest levels in the ISS phenotype. CONCLUSION: The ISS and SSD phenotypes are associated with increased cortisol levels in elderly with MCI. Improving sleep quality and duration and decreasing cortisol levels may delay further cognitive decline.

The landscape of Mucopolysaccharidosis in Southern and Eastern European countries: a survey from 19 specialistic centers.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the picture of disease management in the region and understand ERT implementation. Since the considerable number of MPS IVA patients in the region, particularly adults, the study mainly focused on MPS IVA management and treatment. RESULTS: 19 experts from 14 Southern and Eastern European countries in total responded to the survey. Results outlined a picture of MPS management in the region, with a high number of MPS patients managed in the centers and a high level of care. MPS II was the most prevalent followed by MPS IVA, with a particular high number of adult patients. The study particularly focused on management and treatment of MPS IVA patients. Adherence to current European Guidelines for follow-up of MPS IVA patients is generally adequate, although some important assessments are reported as difficult due to the lack of MPS skilled specialists. Availability of ERT in Southern and Eastern European countries is generally in line with other European regions, even though regulatory, organizational and reimbursement constrains are demanding. CONCLUSIONS: The landscape of MPS in Southern and Eastern European countries is generally comparable to that of other European regions, regarding epidemiology, treatment accessibility and follow up difficulties. However, issues limiting ERT availability and reimbursement should be simplified, to start treatment as early as possible and make it available for more patients. Besides, educational programs dedicated to specialists should be implemented, particularly for pediatricians, clinical geneticists, surgeons, anesthesiologists and neurologists.

Alzheimer's disease research progress in the Mediterranean region: The Alzheimer's Association International Conference Satellite Symposium.

As research and services in the Mediterranean region continue to increase, so do opportunities for global collaboration. To support such collaborations, the Alzheimer's Association was due to hold its seventh Alzheimer's Association International Conference Satellite Symposium in Athens, Greece in 2021. Due to the COVID-19 pandemic, the meeting was held virtually, which enabled attendees from around the world to hear about research efforts in Greece and the surrounding Mediterranean countries. Research updates spanned understanding the biology of, treatments for, and care of people with Alzheimer's disease (AD_ and other dementias. Researchers in the Mediterranean region have outlined the local epidemiology of AD and dementia, and have identified regional populations that may expedite genetic studies. Development of biomarkers is expected to aid early and accurate diagnosis. Numerous efforts have been made to develop culturally specific interventions to both reduce risk of dementia, and to improve quality of life for people living with dementia.

The association of basal cortisol levels with episodic memory in older adults is mediated by executive function.

Elevated basal cortisol levels in elderly may indicate dysregulation of the internal stress-related system, as well as dysfunction and structural alterations in brain structures necessary for cognition, such as hippocampus and prefrontal cortex. Because of the close relation of executive functions and episodic memory processing, in this study we explored whether the association of elevated cortisol levels on episodic memory could be partly attributed to cortisol effects on executive functions. In this cross-sectional study we analyzed data from a sample of 236 community-dwelling older adults from the Cretan Aging Cohort aged 75.56 ± 7.21 years [53 with dementia due to probable Alzheimer's disease, 99 with Mild Cognitive Impairment (MCI) and 84 cognitively non-impaired participants (NI)]. Morning serum cortisol levels were higher in the probable AD as compared to the NI group (p = .031). Mediated regression models in the total sample supported the hypothesis that the negative association of basal cortisol levels with delayed memory was fully mediated by the relation of basal cortisol levels with executive functions and immediate memory (adjusted for age and self-reported depression symptoms). Moderated mediation regression models revealed that the direct effect of cortisol on executive function and the effect of executive function on delayed memory performance were statistically significant among participants diagnosed with MCI, while the immediate memory effect on delayed memory was more pronounced in AD patients, as compared to the NI group. The current findings corroborate neuroimaging research highlighting cortisol effects on executive functions and immediate memory and further suggest that dysregulation of systems involved in these functions may account for the purported detrimental long-term effects of high cortisol levels on delayed memory.

Poor Diet, Long Sleep, and Lack of Physical Activity Are Associated with Inflammation among Non-Demented Community-Dwelling Elderly.

Inflammation in elderly is associated with physical and cognitive morbidity and mortality. We aimed to explore the association of modifiable lifestyle parameters with inflammation among non-demented, community-dwelling elderly. A sub-sample of 117 patients with mild cognitive impairment (MCI, n = 63) and cognitively non-impaired controls (CNI, n = 54) were recruited from a large, population-based cohort in Crete, Greece, of 3140 elders (>60 years old). All participants underwent assessment of medical history/physical examination, extensive neuropsychiatric/neuropsychological evaluation, diet, three-day 24-h actigraphy, subjective sleep, physical activity, and measurement of IL-6 and TNFα plasma levels. Associations between inflammatory markers and diet, objective sleep duration, subjective sleep quality, and lack of physical activity were assessed using multivariate models. Regression analyses in the total group revealed significant associations between TNF-α and low vegetable consumption (p = 0.003), and marginally with objective long nighttime sleep duration (p = 0.04). In addition, IL-6 was associated with low vegetable consumption (p = 0.001) and lack of physical activity (p = 0.001). Poor diet and lack of physical activity appear to be modifiable risk factors of inflammation, whereas long sleep appears to be a marker of increased inflammatory response in elderly. Our findings may have clinical implications given the association of inflammatory response with morbidity, including cognitive decline, and mortality in elderly.

Specific characteristics and current diagnostic and treatment modalities performance of super refractory status epilepticus in children: A comparative study.

OBJECTIVE: Super-refractory status epilepticus (SRSE) is associated with significant morbidity and mortality in children. We explored the clinical spectrum, specific characteristics, and outcome in SRSE patients admitted in a pediatric intensive care unit (PICU) and investigated how well current diagnostic or treatment modalities perform compared to Status Epilepticus (SE) and Refractory SE (RSE) patients. METHODS: Retrospective analysis of PICU patients admitted with convulsive SE during 2009-2019. Eighty-six patients were classified as SE, RSE, and SRSE. New-onset RSE (NORSE) and febrile infection-related epilepsy syndrome (FIRES) were also identified. Functional outcome was evaluated by the modified Rankin scale. RESULTS: Patients with SRSE (n = 20) had longer weaning off anesthetics (p = 0.014), length of stay, mechanical ventilation duration, higher illness severity scores, and poorer outcome compared to SE (n = 13) or RSE (n = 53) patients (all p < 0.001). Diagnosis, mainly expressed by high prevalence of NORSE (n = 13) and FIRES (n = 9), was independently associated with SRSE (p = 0.024). Abnormal MRI findings (p = 0.005), and epilepsy-related pathogenic variants identified by whole-exome sequencing (WES) were mostly found in SRSE patients. Compared to intravenous immunoglobulins and steroid pulses, plasmapheresis and ketogenic diet, more often used in SRSE (p < 0.01), contributed better to seizure control. Only SRSE (AUROC > 0.80, 95% CI = 0.68-0.94, p < 0.001) and diagnosis (AUROC > 0.70, 95% CI = 0.55-0.83, p = 0.02) could predict a poor outcome. CONCLUSION: The majority of SRSE patients are characterized by considerable functional decline and morbidity. WES analysis may reveal epilepsy-related pathogenic variants while early aggressive immunotherapy and/or ketogenic diet might prove beneficial. Multicenter studies for prediction models of outcome are needed.

A novel variant in DYNC1H1 could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum.

Amyotrophic lateral sclerosis (ALS) belongs to the ALS-frontotemporal dementia (FTD) spectrum and is hallmarked by upper and lower motor neuron degeneration. Here, we present a patient with a cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) pathogenic variant who fulfilled the ALS El Escorial criteria, and we review relevant literature. Using whole-exome sequencing, we identified a deleterious point variant in DYNC1H1 (c.4106A > G (p. Q1369R)) as a likely contributor to the ALS phenotype. In silico structural analysis, molecular dynamics simulation, and protein stability analysis predicted that this variant may increase DYNC1H1 protein stability. Moreover, this variant may disrupt binding of the transcription factor TFAP4, thus potentially acting as duon. Because (a) DYNC1H1 forms part of a ubiquitous eukaryotic motor protein complex, and (b) disruption of dynein function by perturbation of the dynein-dynactin protein complex is implicated in other motor neuron degenerative conditions, this variant could disrupt processes like retrograde axonal transport, neuronal migration, and protein recycling. Our findings expand the heterogenous spectrum of the DYNC1H1 pathogenic variant-associated phenotype and prompt further investigations of the role of this gene in ALS.

Variant transthyretin amyloidosis (ATTRv) polyneuropathy in Greece: a broad overview with a focus on non-endemic unexplored regions of the country.

Comprehensive data on variant transthyretin amyloidosis polyneuropathy (ATTRv-PN) in Greece are lacking. We presently provide an overview of ATTRv-PN in Greece, focusing on unexplored non-endemic regions of the country. In total, we identified 57 cases of ATTRv-PN diagnosed over the past 25 years, including 30 from the island of Crete, an apparent endemic region. Patients carried 10 different TTR mutations (C10R; P24S; V30M; R34G; R34T; I68L; A81T; E89Q; E89K and V94A). Carriers of the common V30M mutation constituted 54.3 % of the cohort. A known founder effect for the V30M mutation was present on the island of Crete. Non-endemic cases identified outside the island of Crete are presently reported in more detail. The age of onset ranged from 25 to 77 years, with a mean of 51.1 years. A mean diagnostic delay of 3.2 years was observed. V30M patients had earlier onset and less cardiac involvement than patients carrying other mutations. Genotype-phenotype correlations were largely consistent with published data. We conclude that, with the exception of the Cretan cluster, ATTRv-PN is not endemic in the Greek population. This makes timely diagnosis more challenging, yet absolutely essential given the availability of therapies that can alter the long-term course of the disease.

Genetic cause of epilepsy in a Greek cohort of children and young adults with heterogeneous epilepsy syndromes.

We describe a cohort of 10 unrelated Greek patients (4 females, 6 males; median age 6.5 years, range 2-18 years) with heterogeneous epilepsy syndromes with a genetic basis. In these patients, causative genetic variants, including two novel ones, were identified in 9 known epilepsy-related genes through whole exome sequencing. A patient with glycine encephalopathy was a compound heterozygote for the p.Arg222Cys and the p.Ser77Leu AMT variant. A patient affected with Lafora disease carried the homozygous p.Arg171His EPM2A variant. A de novo heterozygous variant in the GABRG2 gene (p.Pro282Thr) was found in one patient and a pathogenic variant in the GRIN2B gene (p.Gly820Val) in another patient. Infantile-onset lactic acidosis with seizures was associated with the p.Arg446Ter PDHX gene variant in one patient. In two additional epilepsy patients, the p.Ala1662Val and the novel non-sense p.Phe1330Ter SCN1A gene variants were found. Finally, in 3 patients we observed a novel heterozygous missense variant in SCN2A (p.Ala1874Thr), a heterozygous splice site variant in SLC2A1 (c.517-2A>G), as a cause of Glut1 deficiency syndrome, and a pathogenic variant in STXBP1 (p.Arg292Leu), respectively. In half of our cases (patients with variants in the GRIN2B, SCN1A, SCN2A and SLC2A1 genes), a genetic cause with potential management implications was identified.