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Here, we aim to describe COVID-19 pathology across different tissues to clarify the disease's pathophysiology. Lungs, kidneys, hearts, and brains from nine COVID-19 autopsies were compared by using antibodies against SARS-CoV-2, macrophages-microglia, T-lymphocytes, B-lymphocytes, and activated platelets. Alzheimer's Disease pathology was also assessed. PCR techniques were used to verify the presence of viral RNA. COVID-19 cases had a short clinical course (0-32 days) and their mean age was 77.4 y/o. Hypoxic changes and inflammatory infiltrates were present across all tissues. The lymphocytic component in the lungs and kidneys was predominant over that of other tissues (p < 0.001), with a significantly greater presence of T-lymphocytes in the lungs (p = 0.020), which showed the greatest presence of viral antigens. The heart showed scant SARS-CoV-2 traces in the endothelium-endocardium, foci of activated macrophages, and rare lymphocytes. The brain showed scarce SARS-CoV-2 traces, prominent microglial activation, and rare lymphocytes. The pons exhibited the highest microglial activation (p = 0.017). Microthrombosis was significantly higher in COVID-19 lungs (p = 0.023) compared with controls. The most characteristic pathological features of COVID-19 were an abundance of T-lymphocytes and microthrombosis in the lung and relevant microglial hyperactivation in the brainstem. This study suggests that the long-term sequelae of COVID-19 derive from persistent inflammation, rather than persistent viral replication.
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COVID-19 , Trombosis , Anciano , Antígenos Virales , Encéfalo/patología , Humanos , Riñón , Pulmón/patología , Macrófagos , ARN Viral , SARS-CoV-2 , Linfocitos T , Trombosis/patologíaRESUMEN
Alzheimer's disease (AD) and Lewy body dementia (LBD) are two different forms of dementia, but their pathology may involve the same cortical areas with overlapping cognitive manifestations. Nonetheless, the clinical phenotype is different due to the topography of the lesions driven by the different underlying molecular processes that arise apart from genetics, causing diverse neurodegeneration. Here, we define the commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed classical AD and an aggressive form of AD/LBD, respectively, through a neuropathological, genetic (next-generation sequencing), and transcriptomic (RNA-seq) comparison of four different brain areas. A genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in the AD/LBD case, while the AD case showed lower transcriptional dysregulation, with the parietal lobe being the most involved brain area. The hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Our data suggest that there is a link between transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis.
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OBJECTIVES: There is a lack of effective biomarkers for neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia. Extracellular vesicle (EV) RNA cargo can have an interesting potential as a non-invasive biomarker for NDs. However, the knowledge about the abundance of EV-mRNAs and their contribution to neurodegeneration is not clear. METHODS: Large and small EVs (LEVs and SEVs) were isolated from plasma of patients and healthy volunteers (control, CTR) by differential centrifugation and filtration, and RNA was extracted. Whole transcriptome was carried out using next generation sequencing (NGS). RESULTS: Coding RNA (i.e., mRNA) but not long non-coding RNAs (lncRNAs) in SEVs and LEVs of patients with ALS could be distinguished from healthy CTRs and from other NDs using the principal component analysis (PCA). Some mRNAs were found in commonly deregulated between SEVs of patients with ALS and frontotemporal dementia (FTD), and they were classified in mRNA processing and splicing pathways. In LEVs, instead, one mRNA and one antisense RNA (i.e., MAP3K7CL and AP003068.3) were found to be in common among ALS, FTD, and PD. No deregulated mRNAs were found in EVs of patients with AD. CONCLUSION: Different RNA regulation occurs in LEVs and SEVs of NDs. mRNAs and lncRNAs are present in plasma-derived EVs of NDs, and there are common and specific transcripts that characterize LEVs and SEVs from the NDs considered in this study.
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OBJECTIVE: Few studies have examined lockdown effects on the way of living and well-being of older adults stratified by cognitive state. Since cognitive deficits are common in this population, we investigated how cognition influenced their understanding of the pandemic, socio-behavioral responses and lifestyle adaptations during lockdown, and how these factors affected their mood or memory. METHOD: Telephone-based survey involving 204 older adults ≥65 y/o (median: 82) with previous assessments of cognitive state: 164 normal-old (NOLD), 24 mild-neurocognitive disorder (mild-NCD), 18 mild-moderate dementia. A structured questionnaire was developed to assess psychological and socio-behavioral variables. Logistic regression was used to ascertain their effects on mood and memory. RESULTS: With increasing cognitive deficits, understanding of the pandemic and the ability to follow lockdown policies, adapt to lifestyle changes, and maintain remote interactions decreased. Participants with dementia were more depressed; NOLDs remained physically and mentally active but were more bored and anxious. Sleeping and health problems independently increased the likelihood of depression (OR: 2.29; CI: 1.06-4.93; p = 0.034 and OR: 2.45; CI: 1.16-5.16; p = 0.018, respectively); Regular exercise was protective (OR: 0.30; CI: 0.12-0.72; p = 0.007). Worsening subjective memory complaints were associated with dementia (p = 0.006) and depression (p = 0.004); New-onset sleeping problems raised their odds (OR: 10.26; CI: 1.13-93.41; p = 0.039). Finally, >40% with health problems avoided healthcare mainly due to fear of contagion. DISCUSSION: NOLD and mild-NCD groups showed similar mood-behavioral profiles suggesting better tolerance of lockdown. Those with dementia were unable to adapt and suffered from depression and cognitive complaints. To counteract lockdown effects, physical and mental activities and digital literacy should be encouraged.
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COVID-19 , Anciano , Cognición , Control de Enfermedades Transmisibles , Humanos , Estilo de Vida , SARS-CoV-2RESUMEN
Since the association of SARS-Cov-2 infection with Nervous System (NS) manifestations, we performed RNA-sequencing analysis in Frontal Cortex of COVID-19 positive or negative individuals and affected or not by Dementia individuals. We examined gene expression differences in individuals with COVID-19 and Dementia compared to Dementia only patients by collecting transcript counts in each sample and performing Differential Expression analysis. We found eleven genes satisfying our significance criteria, all of them being protein coding genes. These data are suitable for integration with supplemental samples and for analysis according to different individuals' classification. Also, differential expression evaluation may be implemented with other scientific purposes, such as research of unannotated genes, mRNA splicing and genes isoforms. The analysis of Differential Expressed genes in COVID-19 positive patients compared to non-COVID-19 patients is published in: S. Gagliardi, E.T. Poloni, C. Pandini, M. Garofalo, F. Dragoni, V. Medici, A. Davin, S.D. Visonà, M. Moretti, D. Sproviero, O. Pansarasa, A. Guaita, M. Ceroni, L. Tronconi, C. Cereda, Detection of SARS-CoV-2 genome and whole transcriptome sequencing in frontal cortex of COVID-19 patients., Brain. Behav. Immun. (2021). https://doi.org/10.1016/j.bbi.2021.05.012.
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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Although its etiology is still unknown, many genes have been found to be implicated in ALS pathogenesis. The Cu/Zn superoxide dismutase (SOD1) gene was the first to be identified. Currently, more than 230 mutations in the SOD1 gene have been reported. p.D90A (p. Asp90Ala) is the most common SOD1 mutation worldwide. It shows both autosomal and recessive inheritance in different populations. To date, five Italian patients with the heterozygous p.D90A mutation have been reported. None of them complained of laryngological symptoms as the initial manifestation of ALS, although they had atypical clinical features. We describe a long-survival patient carrying heterozygous p.D90A mutation who presented with severe laryngospasm due to bilateral vocal cord paralysis. We suggest that genetic analysis may help to diagnose ALS with insidious onset like hoarseness, laryngospasm, and other type of voice disturbances.
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The actual role of SARS-CoV-2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS-CoV-2 or by pre-existing conditions. Findings of 9 Coronavirus disease 2019 (COVID-19) cases and 6 matched non-COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS-CoV-2, lymphocytes, astrocytes, endothelium, and microglia. A semi-quantitative scoring was applied to grade microglial activation. Thal-Braak stages and the presence of small vessel disease were determined in all cases. COVID-19 cases had a relatively short clinical course (0-32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID-19 cases showed non-SARS-CoV-2-specific changes including hypoxic-agonal alterations, and a variable degree of neurodegeneration and/or pre-existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS-CoV-2 were detected. Microglial activation in the brainstem was significantly greater in COVID-19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS-CoV-2 infection. In COVID-19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer's pathology and COVID-19, cortical neuroinflammation is not related to COVID-19 per se but mostly to pre-existing neurodegeneration. COVID-19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS-CoV-2-specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID-19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the "COVID-19 encephalopathic syndrome" in the elderly.
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COVID-19/patología , Demencia/virología , Microglía/patología , Enfermedades del Sistema Nervioso/virología , Anciano , Anciano de 80 o más Años , Astrocitos/patología , Encéfalo/patología , COVID-19/psicología , Estudios de Casos y Controles , Demencia/patología , Demencia/psicología , Femenino , Humanos , Masculino , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/psicología , SARS-CoV-2/aislamiento & purificaciónRESUMEN
SARS-Cov-2 infection is frequently associated with Nervous System manifestations. However, it is not clear how SARS-CoV-2 can cause neurological dysfunctions and which molecular processes are affected in the brain. In this work, we examined the frontal cortex tissue of patients who died of COVID-19 for the presence of SARS-CoV-2, comparing qRT-PCR with ddPCR. We also investigated the transcriptomic profile of frontal cortex from COVID-19 patients and matched controls by RNA-seq analysis to characterize the transcriptional signature. Our data showed that SARS-CoV-2 could be detected by ddPCR in 8 (88%) of 9 examined samples while by qRT-PCR in one case only (11%). Transcriptomic analysis revealed that 11 genes (10 mRNAs and 1 lncRNA) were differential expressed when frontal cortex of COVID-19 patients were compared to controls. These genes fall into categories including hypoxia, hemoglobin-stabilizing protein, hydrogen peroxide processes. This work demonstrated that the quantity of viral RNA in frontal cortex is minimal and it can be detected only with a very sensitive method (ddPCR). Thus, it is likely that SARS-CoV-2 does not actively infect and replicate in the brain; its topography within encephalic structures remains uncertain. Moreover, COVID-19 may have a role on brain gene expression, since we observed an important downregulation of genes associated to hypoxia inducting factor system (HIF) that may inhibit the capacity of defense system during infection and oxigen deprivation, showing that hypoxia, well known multi organ condition associated to COVID-19, also marked the brain.
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COVID-19 , SARS-CoV-2 , Lóbulo Frontal , Humanos , Transcriptoma , Secuenciación del ExomaRESUMEN
Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different miRNA signatures in plasma derived LEVs and SEVs of Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients. LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and differential centrifugation and RNA was extracted. Small RNAs libraries were carried out by Next Generation Sequencing (NGS). MiRNAs discriminate all NDs diseases from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were instead linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway. LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading of the disease. The study of common and different miRNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.
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MicroARN Circulante/sangre , Vesículas Extracelulares/metabolismo , Perfilación de la Expresión Génica , Enfermedades Neurodegenerativas/sangre , Transducción de Señal , Anciano , Anciano de 80 o más Años , MicroARN Circulante/genética , Vesículas Extracelulares/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/genéticaRESUMEN
BACKGROUND: Frontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases often considered as a continuum from clinical, epidemiologic, and genetic perspectives. We used localized brain volume alterations to evaluate common and specific features of FTSD, FTSD-ALS, and ALS patients to further understand this clinical continuum. METHODS: We used voxel-based morphometry on structural magnetic resonance images to localize volume alterations in group comparisons: patients (20 FTSD, seven FTSD-ALS, and 18 ALS) versus healthy controls (39 CTR), and patient groups between themselves. We used mean whole-brain cortical thickness ( C T ¯ ) to assess whether its correlations with local brain volume could propose mechanistic explanations of the heterogeneous clinical presentations. We also assessed whether volume reduction can explain cognitive impairment, measured with frontal assessment battery, verbal fluency, and semantic fluency. RESULTS: Common (mainly frontal) and specific areas with reduced volume were detected between FTSD, FTSD-ALS, and ALS patients, confirming suggestions of a clinical continuum, while at the same time defining morphological specificities for each clinical group (e.g., a difference of cerebral and cerebellar involvement between FTSD and ALS). C T ¯ values suggested extensive network disruption in the pathological process, with indications of a correlation between cerebral and cerebellar volumes and C T ¯ in ALS. The analysis of the neuropsychological scores indeed pointed toward an important role for the cerebellum, along with fronto-temporal areas, in explaining impairment of executive, and linguistic functions. CONCLUSION: We identified common elements that explain the FTSD-ALS clinical continuum, while also identifying specificities of each group, partially explained by different cerebral and cerebellar involvement.
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During the recent coronavirus disease 2019 (COVID-19) outbreak in Northern Italy, we observed a 57-year-old man developing acute motor-sensory axonal neuropathy, a variant of Guillain-Barré syndrome (GBS), 12 days after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Similarly to other bacterial and viral infections, dysregulation of the immune system due to post-infectious mechanisms, such as the molecular mimicry, could lead to an indirect damage of the peripheral nervous system related to SARS-CoV-2. GBS causes motor dysfunctions that are not easily recognizable in non-neurological settings or in patients requiring ventilatory assistance. Several reports also suggested that GBS and Miller Fisher syndrome (MFS) could be neurological complications of COVID-19. Therefore, we performed a review of the 29 articles so far published, describing 33 GBS cases and five MFS cases associated with SARS-CoV-2 infection. We recommend awareness of this rare, but treatable, neurological syndrome, which may also determine a sudden and otherwise unexplained respiratory deterioration in COVID-19 patients.
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BACKGROUND: Delirium may be one of the presenting symptoms of COVID-19, complicating diagnosis and care of elderly patients with dementia. We aim to identify the prevalence and prognostic significance of delirium as the sole onset manifestation of COVID-19. METHODS: This is a retrospective single-centre study based on review of medical charts, conducted during the outbreak peak (March 27-April 18, 2020) in a Lombard dementia facility, including 59 elderly subjects with dementia and laboratory-confirmed COVID-19. FINDINGS: Of the 59 residents, 57 (96â 6%) tested positive (mean age: 82â 8; women: 66â 7%). Comorbidities were present in all participants, with 18/57 (31â 6%) having three or more concomitant diseases. Delirium-Onset COVID-19 (DOC) was observed in 21/57 (36â 8%) subjects who were chiefly older (mean age: 85â 4 y/o) and with multiple comorbidities. Eleven/21 DOC patients (52â 4%) had hypoactive delirium, while hyperactive delirium occurred in ten/21 (47â 6%). Lymphopenia was present in almost all subjects (median: 1â 3 × 109/L). Overall mortality rate was 24â 6% (14/57) and dementia severity per se had no impact on short-term mortality due to COVID-19. DOC was strongly associated with higher mortality (p<0â 001). Also, DOC and male gender were independently associated with increased risk of mortality (OR: 17â 0, 95% CI: 2â 8-102â 7, p = 0â 002 and 13â 6, 95% CI: 2â 3-79â 2, p = 0â 001 respectively). INTERPRETATION: Delirium occurrence in the elderly with dementia may represent a prodromal phase of COVID-19, and thus deserves special attention, especially in the presence of lymphopenia. Hypoxia and a severe inflammatory state may develop subsequently. DOC cases have higher short-term mortality rate. FUNDING: None.
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BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) was traditionally described as a disease restricted to the motor system. However, recent findings suggested that it also affects cognition, especially executive functions, social cognition, language and pragmatics. A relevant issue in current research is thus the description of the cognitive phenotype of ALS and the identification of the most vulnerable aspects. AIMS: The focus was on a communicative phenomenon placed at the crossroads of pragmatic and other cognitive domains, namely humour, which till now has been poorly explored in ALS. The first aim was to investigate whether ALS is associated with impairments in understanding and appreciating jokes. The second aim was to explore the predictors of humour comprehension and appreciation in patients, to confirm the involvement of pragmatic skills and to explore the role of other cognitive and clinical aspects. METHODS & PROCEDURES: A total of 30 non-demented patients with ALS and 27 controls were assessed with a task of verbal humour comprehension and appreciation, including two types of jokes: phonological and mental. We also administered a battery of pragmatic and other language tasks, and cognitive and socio-cognitive tasks. Mixed-effects models were used to test differences in the humour task between the two groups. Multiple regressions determined the best predictors of humour comprehension and appreciation in patients. OUTCOMES & RESULTS: Patients obtained lower comprehension accuracy scores than controls in the humour task, independently of the type of joke. Conversely, patients and controls did not differ in joke appreciation and both rated mental jokes as funnier than the phonological ones. Patients' comprehension accuracy was predicted by pragmatic skills and ALS severity, whereas appreciation was predicted by several clinical variables and, to a smaller extent, by language skills. CONCLUSIONS & IMPLICATIONS: The findings suggest that humour is a very vulnerable aspect in ALS, and that impairment in humour comprehension might be part of the larger cognitive impairment, being linked to pragmatic impairment. Clinical variables were also important, especially in relation to humour appreciation. More generally, these data speak in favour of pragmatics as a relevant aspect to sketch the cognitive phenotype of ALS. On the practical level, these findings point to the need of supporting communication at large, not only motor-related aspects such as dysarthria but also social-pragmatic aspects such as understanding jokes, to increase well-being in ALS. What this paper adds What is already known on this subject The literature of the last decades has shown that ALS comes with impairment in several cognitive domains, affecting especially executive functions as well as language. There is also initial evidence that the pragmatics of communication and humour comprehension are impaired, although non-serious talk has been documented in conversational interaction among people with ALS. What this paper adds to existing knowledge This study offers compelling evidence of an impairment in the comprehension of jokes in ALS, whereas the appreciation of joke funniness seems to be spared. The study also highlights the interplay of cognitive factors (especially pragmatics) and clinical factors (related to disease severity) in predicting the patients' performance in the humour task. What are the potential or actual clinical implications of this work? The study's findings call for the need of increased awareness among scholars as well as practitioners and caregivers of the profile of humour comprehension and appreciation in ALS. On a practical level, we highlight the need of assessing humour comprehension and adapting the communicative style accordingly. Second, we recommend that intervention programmes targeting communication in ALS go beyond speech-related difficulties and include pragmatic aspects such as humour. Considering the important communicative and social function of humour, as well as its use as a coping strategy, humour interventions are key to improve the quality of life of individuals with ALS.
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Esclerosis Amiotrófica Lateral/psicología , Trastornos del Conocimiento/psicología , Trastorno de Comunicación Social/psicología , Ingenio y Humor como Asunto/psicología , Anciano , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Comprensión , Función Ejecutiva , Femenino , Humanos , Pruebas del Lenguaje , Lingüística , Masculino , Persona de Mediana Edad , Fenotipo , Cognición Social , Trastorno de Comunicación Social/diagnóstico , Trastorno de Comunicación Social/etiología , Conducta VerbalRESUMEN
In a constantly aging population, the prevalence of neurodegenerative disorders is expected to rise. Understanding disease mechanisms is the key to find preventive and curative measures. The most effective way to achieve this is through direct examination of diseased and healthy brain tissue. The authors present a protocol to obtain, process, characterize and store good quality brain tissue donated by individuals registered in an antemortem brain donation program. The donation program includes a face-to-face empathic approach to people, a collection of complementary clinical, biological, social and lifestyle information and serial multi-dimensional assessments over time to track individual trajectories of normal aging and cognitive decline. Since many neurological diseases are asymmetrical, our brain bank offers a unique protocol for slicing fresh specimens. Brain sections of both hemispheres are alternately frozen (at -80 °C) or fixed in formalin; a fixed slice on one hemisphere corresponds to a frozen one on the other hemisphere. With this approach, a complete histological characterization of all frozen material can be obtained, and omics studies can be performed on histologically well-defined tissues from both hemispheres thus offering a more complete assessment of neurodegenerative disease mechanisms. Correct and definite diagnosis of these diseases can only be achieved by combining the clinical syndrome with the neuropathological evaluation, which often adds important etiological clues necessary to interpret the pathogenesis. This method can be time consuming, expensive and limited as it only covers a limited geographical area. Regardless of its limitations, the high degree of characterization it provides can be rewarding. Our ultimate goal is to establish the first Italian Brain Bank, all the while emphasizing the importance of neuropathologically verified epidemiological studies.
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Envejecimiento , Encéfalo/citología , Manejo de Especímenes/métodos , Bancos de Tejidos , Anciano , Envejecimiento/patología , Encéfalo/patología , Humanos , Enfermedades Neurodegenerativas/patologíaRESUMEN
Conflicting results about alterations of plasma amino acid (AA) levels are reported in subjects with Alzheimer's disease (AD). The current study aimed to provide more homogeneous AA profiles and correlations between AAs and cognitive tests. Venous plasma AAs were measured in 54 fasting patients with AD (37 males, 17 females; 74.63 ± 8.03 yrs; 3.2 ± 1.9 yrs from symptom onset). Seventeen matched subjects without neurodegenerative symptoms (NNDS) served as a control group (C-NNDS). Patients were tested for short-term verbal memory and attention capacity and stratified for nutritional state (Mini Nutritional Assessment, MNA). Compared to C-NNDS, patients exhibited lower plasma levels of aspartic acid and taurine (p < 0.0001) and higher 3-methylhistidine (p < 0.0001), which were independent of patients' MNA. In comparison to normonourished AD, the patients at risk of and with malnutrition showed a tendency towards lower ratios of Essential AAs/Total AAs, Branched-chain AAs/Total AAs, and Branched-chain AAs/Essential AAs. Serine and histidine were positively correlated with verbal memory and attention capacity deficits, respectively. Total AAs negatively correlated with attention capacity deficits. Stratifying patients with AD for MNA may identify a dual pattern of altered AAs, one due to AD per se and the other linked to nutritional state. Significant correlations were observed between several AAs and cognitive tests.
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Enfermedad de Alzheimer/sangre , Aminoácidos/sangre , Estado Nutricional , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Atención , Femenino , Histidina/sangre , Humanos , Masculino , Desnutrición/sangre , Desnutrición/complicaciones , Memoria , Trastornos de la Memoria/sangre , Evaluación Nutricional , Serina/sangreRESUMEN
INTRODUCTION: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function. METHODS AND ANALYSIS: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals. TRIAL REGISTRATION NUMBER: EUDRACT 2017-004459-21; NCT03693781; Pre-results.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Autofagia/fisiología , Colchicina/uso terapéutico , Proteínas del Choque Térmico HSP20/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Proteostasis/efectos de los fármacos , Adulto , Anciano , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/fisiopatología , Autofagia/efectos de los fármacos , Biomarcadores , Ensayos Clínicos Fase II como Asunto , Colchicina/farmacocinética , Proteínas de Unión al ADN/antagonistas & inhibidores , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Proteínas de Choque Térmico , Humanos , Masculino , Persona de Mediana Edad , Chaperonas Moleculares , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Fármacos Neuroprotectores/farmacocinética , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Adulto JovenRESUMEN
The lack of biomarkers in Amyotrophic Lateral Sclerosis (ALS) makes it difficult to determine the stage of the disease in patients and, therefore, it delays therapeutic trials. Microvesicles (MVs) are possible biomarkers implicated in physiological and pathological functions, however, their role in ALS remains unclear. We investigated whether plasma derived microvesicles could be overrepresented in a group of 40 patients affected by ALS compared to 28 Alzheimer's Disease (AD) patients and 36 healthy volunteers. Leukocyte derived MVs (LMVs) compared to endothelial, platelet, erythrocyte derived MVs, were mostly present in ALS patients compared to AD patients and healthy donors. Correlation analysis corrected for the presence of confounding variables (riluzole, age at onset, site of onset, gender) was tested between PRL (Progression Rate at the Last visit) and LMVs, and a statistically significant value was found (Pearson partial correlation r = 0.407, p = 0.006). We also investigated SOD1, TDP-43 intravesicular protein level in LMVs. Misfolded SOD1 was selectively transported by LMVs and its protein level was associated with the percentage of LMVs in slow progressing patients (r = 0.545, p = 0.033). Our preliminary findings suggest that LMVs are upregulated in ALS patients and they can be considered possible markers of disease progression.