RESUMEN
Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which act as intracellular second messengers for signal transduction pathways and modulate various processes in the central nervous system. Recent discoveries that mutations in genes encoding different PDEs, including PDE10A, are responsible for rare forms of chorea in children led to the recognition of an emerging role of PDEs in the field of pediatric movement disorders. A comprehensive literature review of all reported cases of PDE10A mutations in PubMed and Web of Science was performed in English. We included eight studies, describing 31 patients harboring a PDE10A mutation and exhibiting a hyperkinetic movement disorder with onset in infancy or childhood. Mutations in both GAF-A, GAF-B regulatory domains and outside the GAF domains of the PDE10A gene have been reported to cause hyperkinetic movement disorders. In general, patients with homozygous mutations in either GAF-A domain of PDE10A present with a more severe phenotype and at an earlier age but without any extensive abnormalities of the striata compared with patients with dominant variants in GAF-B domain, indicating that dominant and recessive mutations have different pathogenic mechanisms. PDE10A plays a key role in regulating control of striato-cortical movement. Comprehension of the molecular mechanisms within the cAMP and cGMP signaling systems caused by PDE10A mutations may inform novel therapeutic strategies that could alleviate symptoms in young patients affected by these rare movement disorders.
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Hipercinesia , Mutación , Hidrolasas Diéster Fosfóricas , Humanos , Hidrolasas Diéster Fosfóricas/genética , Hipercinesia/genética , NiñoRESUMEN
(1) Background: It is important to monitor the body core temperature (Tc) of individuals with chronic heart failure (CHF) during rest or exercise, as they are susceptible to complications. Gastrointestinal capsules are a robust indicator of the Tc at rest and during exercise. A practical and non-invasive sensor called CALERA Research was recently introduced, promising accuracy, sensitivity, continuous real-time analysis, repeatability, and reproducibility. This study aimed to assess the validity of the CALERA Research sensor when monitoring patients with CHF during periods of rest, throughout brief cardiopulmonary exercise testing, and during their subsequent recovery. (2) Methods: Twelve male CHF patients volunteered to participate in a 70-min protocol in a laboratory at 28 °C and 39% relative humidity. After remaining calm for 20 min, they underwent a symptom-limited stress test combined with ergospirometry on a treadmill, followed by 40 min of seated recovery. The Tc was continuously monitored by both Tc devices. (3) Results: The Tc values from the CALERA Research sensor and the gastrointestinal sensor showed no associations at rest (r = 0.056, p = 0.154) and during exercise (r = -0.015, p = 0.829) and a weak association during recovery (r = 0.292, p < 0.001). The Cohen's effect size of the differences between the two Tc assessment methods for rest, exercise, and recovery was 1.04 (large), 0.18 (none), and 0.45 (small), respectively. The 95% limit of agreement for the CALERA Research sensor was -0.057 ± 1.03 °C. (4) Conclusions: The CALERA sensor is a practical and, potentially, promising device, but it does not provide an accurate Tc estimation in CHF patients at rest, during brief exercise testing, and during recovery.
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Ejercicio Físico , Insuficiencia Cardíaca , Humanos , Masculino , Reproducibilidad de los Resultados , Temperatura , Temperatura Corporal , Insuficiencia Cardíaca/diagnóstico , Prueba de EsfuerzoRESUMEN
Parkinson's disease (PD) is characterized by substantial phenotypic heterogeneity that limits the disease prognosis and patient's counseling, and complicates the design of further clinical trials. There is an unmet need for the development and validation of biomarkers for the prediction of the disease course. In this study, we utilized flow cytometry and in vitro approaches on peripheral blood cells and isolated peripheral blood mononuclear cell (PBMC)-derived macrophages to characterize specific innate immune populations in PD patients versus healthy donors. We found a significantly lower percentage of B lymphocytes and monocyte populations in PD patients. Monocytes in PD patients were characterized by a higher CD40 expression and on-surface expression of the type I membrane glycoprotein sortilin, which showed a trend of negative correlation with the age of the patients. These results were further investigated in vitro on PBMC-derived macrophages, which, in PD patients, showed higher sortilin expression levels compared to cells from healthy donors. The treatment of PD-derived macrophages with oxLDL led to higher foam cell formation compared to healthy donors. In conclusion, our results support the hypothesis that surface sortilin expression levels on human peripheral monocytes may potentially be utilized as a marker of Parkinson's disease and may segregate the sporadic versus the genetically induced forms of the disease.
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Enfermedad de Parkinson , Humanos , Leucocitos Mononucleares/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Biomarcadores/metabolismoRESUMEN
OBJECTIVE: To prospectively assess the efficacy and safety of fremanezumab for migraine prophylaxis in patients with failure of at least three previous preventive treatments. Changes in disability as quality-of-life outcomes after fremanezumab treatment were also examined. METHODS: Two hundred and four patients with either high-frequency EM (HFEM) or chronic migraine (CM), who attained at least three consecutive monthly sessions with fremanezumab 225 mg and otherwise met the inclusion criteria, were included in the study. The crude response (at least 50% reduction in monthly headache days [MHD]) rates to fremanezumab were assessed. Scores in the following efficacy outcomes were then compared from baseline to the last efficacy evaluation follow-up: (i) MHD, (ii) monthly days with moderate/severe peak headache intensity, and (iii) monthly days with intake of abortive medication. The disability was evaluated with the Migraine Disability Assessment; the quality of life (QOL) status was assessed with the Headache Impact-6 Test, and the EQ-5D questionnaire. RESULTS: In the majority of HFEM cases (n = 81/97; 83.5%) and CM patients (n = 67/107; 62.6%), fremanezumab proved effective in reducing the MHDs by at least 50% and was associated with clinically meaningful improvement in all other efficacy variables. The migraine-related disability experienced by our patients decreased and their QOL increased. We recorded just 36 cases reporting mild adverse events, including pain, rash or pruritus (n = 26), flu-like symptoms (n = 8), and hair loss (n = 2). CONCLUSION: With our prospective results, we provide further real-world data to support the favorable benefit/risk profile of fremanezumab in the prophylaxis of both HFEM and CM.
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Trastornos Migrañosos , Calidad de Vida , Humanos , Grecia , Estudios Prospectivos , Resultado del Tratamiento , Método Doble Ciego , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/prevención & control , Trastornos Migrañosos/diagnóstico , Cefalea , Sistema de RegistrosRESUMEN
BACKGROUND AND PURPOSE: Lifestyle factors have been implicated in the long-lasting neurodegenerative process in prodromal Parkinson's disease (pPD). The aim was to investigate the associations between adherence to a Mediterranean diet (MeDi) and longitudinal changes of pPD probability and the development of Parkinson's disease (PD) or pPD in a Mediterranean older population. METHODS: Data from the Hellenic Longitudinal Investigation of Aging and Diet cohort (community-dwelling individuals, aged ≥ 65 years) were used. A detailed food frequency questionnaire was used to evaluate dietary intake and calculate MeDi adherence score, ranging from 0 to 55, with higher scores indicating higher adherence. The probability of pPD was calculated according to the updated Movement Disorder Society research criteria. RESULTS: In all, 1047 non-PD/dementia with Lewy bodies (DLB) participants were followed for 3 ± 1 years. MeDi adherence was associated with lower increase in pPD probability over time (b = -0.003, 95% confidence interval -0.006 to -0.001, p = 0.010). Forty-nine participants had incident possible/probable pPD (i.e., pPD probability ≥ 30%). Compared to the participants in the lowest quartile of MeDi adherence, those in the higher quartiles had an approximately 60%-70% lower risk for possible/probable pPD (p for trend 0.003). MeDi-pPD associations were driven by both motor and non-motor pPD markers and not from risk markers. Also, 21 participants were diagnosed with PD/DLB at follow-up. For each unit increase in the MeDi score, there was a 9%-10% lower risk for PD/DLB (hazard ratio 0.906 [95% confidence interval 0.823-0.997], p = 0.044). CONCLUSIONS: Mediterranean diet adherence is associated with lower increase in pPD probability over time and lower possible/probable pPD and PD/DLB incidence in older Mediterranean people. More studies are needed to confirm our results in other populations.
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Dieta Mediterránea , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Humanos , Anciano , Estudios Longitudinales , Enfermedad de Parkinson/complicaciones , Enfermedad por Cuerpos de Lewy/complicaciones , ProbabilidadRESUMEN
Background and Objectives: Rare diseases (RDs) are life-threatening or chronically impairing conditions that affect about 6% of the world's population. RDs are often called 'orphan' diseases, since people suffering from them attract little support from national health systems. Aim: The aim of this study is to describe the clinical characteristics of, and the available laboratory examinations for, patients who were hospitalized in a tertiary referral center and finally received a diagnosis associated with a Rare Neurological Disease (RND). Materials and Methods: Patients that were hospitalized in our clinic from 1 January 2014 to 31 March 2022 and were finally diagnosed with an RND were consecutively included. The RND classification was performed according to the ORPHAcode system. Results: A total of 342 out of 11.850 (2.9%) adult patients admitted to our department during this period received a diagnosis associated with an RND. The most common diagnosis (N = 80, 23%) involved an RND presenting with dementia, followed by a motor neuron disease spectrum disorder (N = 64, 18.7%). Family history indicative of an RND was present in only 21 patients (6.1%). Fifty-five (16%) people had previously been misdiagnosed with another neurological condition. The mean time delay between disease onset and diagnosis was 4.24 ± 0.41 years. Conclusions: Our data indicate that a broad spectrum of RNDs may reach a tertiary Neurological Center after a significant delay. Moreover, our data underline the need for a network of reference centers, both at a national and international level, expected to support research on the diagnosis and treatment of RND.
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Enfermedades del Sistema Nervioso , Enfermedades Raras , Adulto , Humanos , Enfermedades Raras/epidemiología , Centros de Atención Terciaria , HospitalizaciónRESUMEN
BACKGROUND: A decrease in glutathione (GSH) levels is considered one of the earliest biochemical changes in Parkinson's disease (PD). OBJECTIVE: The authors explored the potential role of plasma GSH as a risk/susceptibility biomarker for prodromal PD (pPD) by examining its longitudinal associations with pPD probability trajectories. METHODS: A total of 405 community-dwelling participants (median age [interquartile range] = 73.2 [7.41] years) without clinical features of parkinsonism were followed for a mean (standard deviation) of 3.0 (0.9) years. RESULTS: A 1 µmol/L increase in plasma GSH was associated with 0.4% (95% confidence interval [CI], 0.1%-0.7%; P = 0.017) less increase in pPD probability for 1 year of follow-up. Compared with participants in the lowest GSH tertile, participants in the highest GSH tertile had a 12.9% (95% CI, 22.4%-2.2%; P = 0.020) slower rate of increase of pPD probability for 1 year of follow-up. CONCLUSION: Plasma GSH was associated with pPD probability trajectories; therefore, it might assist in the identification of individuals who are likely to reach the threshold for pPD diagnosis more rapidly. © 2021 International Parkinson and Movement Disorder Society.
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Glutatión , Enfermedad de Parkinson , Síntomas Prodrómicos , Anciano , Glutatión/sangre , Humanos , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , ProbabilidadRESUMEN
BACKGROUND: Differences have been noted in the clinical presentation and mutational spectrum of CADASIL among various geographical areas. The aim of the present study was to investigate the mode of clinical presentation and genetic mutations reported in Greece. METHODS: After a systematic literature search, we performed a pooled analysis of all published CADASIL cases from Greece. RESULTS: We identified 14 studies that reported data from 14 families comprising 54 patients. Migraine with aura was reported in 39%, ischemic cerebrovascular diseases in 68%, behavioral-psychiatric symptoms in 47% and cognitive decline in 60% of the patients. The mean (±SD) age of onset for migraine with aura, ischemic cerebrovascular diseases, behavioral-psychiatric symptoms and cognitive decline was 26.2 ± 8.7, 49.3 ± 14.6, 47.9 ± 9.4 and 42.9 ± 10.3, respectively; the mean age at disease onset and death was 34.6 ± 12.1 and 60.2 ± 11.2 years. With respect to reported mutations, mutations in exon 4 were the most frequently reported (61.5% of all families), with the R169C mutation being the most common (30.8% of all families and 50% of exon 4 mutations), followed by R182C mutation (15.4% of all families and 25% of exon 4 mutations). CONCLUSIONS: The clinical presentation of CADASIL in Greece is in accordance with the phenotype encountered in Caucasian populations, but differs from the Asian phenotype, which is characterized by a lower prevalence of migraine and psychiatric symptoms. The genotype of Greek CADASIL pedigrees is similar to that of British pedigrees, exhibiting a high prevalence of exon 4 mutations, but differs from Italian and Asian populations, where mutations in exon 11 are frequently encountered.
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CADASIL , Adulto , Anciano , CADASIL/diagnóstico , CADASIL/epidemiología , CADASIL/genética , Grecia/epidemiología , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Mutación/genética , Receptor Notch3/genética , Receptores Notch/genética , Adulto JovenRESUMEN
One of the major mediators of neuroinflammation in PD is tumour necrosis factor alpha (TNF-α), which, similar to other cytokines, is produced by activated microglia and astrocytes. Although TNF-α can be neuroprotective in the brain, long-term neuroinflammation and TNF release can be harmful, having a neurotoxic role that leads to death of oligodendrocytes, astrocytes, and neurons and, therefore, is associated with neurodegeneration. Apart from cytokines, a wide family of molecules with homologous structures, namely chemokines, play a key role in neuro-inflammation by drawing cytotoxic T-lymphocytes and activating microglia. The objective of the current study was to examine the levels of the serum TNF-α and CCL2 (Chemokine (C-C motif) ligand 2), also known as MCP-1 (Monocyte Chemoattractant Protein-1), in PD patients compared with healthy controls. We also investigated the associations between the serum levels of these two inflammatory mediators and a number of clinical symptoms, in particular, disease severity and cognition. Such an assessment may point to their prognostic value and provide some treatment hints. PD patients with advanced stage on the Hoehn-Yahr scale showed an increase in TNF-α levels compared with PD patients with stages 1 and 2 (p = 0.01). Additionally, the UPDRS score was significantly associated with TNF-α levels. CCL2 levels, however, showed no significant associations.
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Quimiocina CCL2 , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico , Factor de Necrosis Tumoral alfa , Enfermedades Neuroinflamatorias , Quimiocinas , Citocinas , Gravedad del PacienteRESUMEN
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.
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COVID-19 , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Trastornos Parkinsonianos , COVID-19/complicaciones , Comunicación Celular , Humanos , Enfermedad de Parkinson/metabolismo , Trastornos Parkinsonianos/etiología , Trastornos Parkinsonianos/patología , ARN Viral , SARS-CoV-2 , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Small vessel disease (SVD), and most specifically hereditary forms like CADASIL and cerebral amyloid angiopathy (hCAA), are conditions of increasing clinical importance. We report a rare case of hCAA in a Greek family that presented with a CADASIL clinical and neuroimaging phenotype. METHODS: A 65-year-old man was admitted with recurrent transient episodes of right leg numbness. The patient's medical history started at the age of 50 years with depression and behavioral disorders. His family history was positive for stroke (father), dementia (father and brother), migraine (daughter) and depression (father and daughter). RESULTS: Neurological examination disclosed anomic aphasia with severely impaired cognitive status, and brisk reflexes. Brain computed tomography and magnetic resonance imaging showed CADASIL-like leukoencephalopathy (hyperintense lesions in bilateral temporopolar area, external capsule, thalami, centrum semiovale and superior frontal regions) with occipital calcifications and cerebral microbleeds. Screen for variants in NOTCH3 gene was negative. Exome sequencing revealed a novel pathogenic mutation for hCAA. CONCLUSIONS: We report a novel amyloid precursor protein mutation which results in a CADASIL-like clinical phenotype (progressive cognitive and motor decline, stroke, migraine and behavioral disorders) and CADASIL-leukoencephalopathy coupled with occipital calcifications. Earlier recognition and swift hCAA diagnosis may prompt rational preventive and potential disease-modifying interventions.
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CADASIL , Angiopatía Amiloide Cerebral Familiar , Anciano , CADASIL/diagnóstico por imagen , CADASIL/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Receptor Notch3/genéticaRESUMEN
Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with isolated and complex early-onset generalized dystonia. We describe clinico-genetic features on a Greek patient with a novel de novo variant and demonstrate the phenotypic spectrum of KMT2B variants. We performed whole exome sequencing (WES), in a Greek patient with sporadic generalized dystonia. Additionally, we performed a systematic review of all published cases with KMT2B variants. The patient presented with isolated and mild generalized dystonia. We identified a novel splice site variant that was confirmed by Sanger sequencing and was not found in parents. This is the first reported KMT2B variant, in the Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to few cases in many different ethnic groups worldwide via exome sequencing. In the systematic review, we evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various KMT2B variants.
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Distonía/genética , N-Metiltransferasa de Histona-Lisina/genética , Isoformas de Proteínas/genética , Adulto , Edad de Inicio , Distonía/patología , Exoma/genética , Femenino , Estudios de Asociación Genética , Grecia , Histonas/genética , Humanos , Masculino , Chaperonas Moleculares/genética , Mutación/genética , Linaje , Fenotipo , Secuenciación del ExomaRESUMEN
Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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Complejo 4 de Proteína Adaptadora/genética , Cuerpo Calloso/diagnóstico por imagen , Imagen por Resonancia Magnética/tendencias , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Sistema de Registros , Adulto JovenRESUMEN
A 67-year-old male photographer who used traditional cameras that necessitated monocular focusing developed intermittent blepharospasms, evident only during and shortly after the voluntary contraction of the left eyelids while using the camera, a form of a task-specific blepharospasm. The spasms gradually progressed to involve the entire hemiface resulting in a task-specific hemifacial spasm that eventually evolved into a persistent hemifacial spasm. Our case report highlights the fact that focal dystonia may also develop in the facial muscles following chronic and repetitive muscle contractions, such as those performed by an older photographer who used traditional cameras that necessitated monocular focusing. To our knowledge, hemifacial spasm has not yet been recognized as a form of focal, task-specific dystonia. Moreover, occupational, focal dystonia has not been described in photographers.
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Blefaroespasmo , Trastornos Distónicos , Espasmo Hemifacial , Anciano , Blefaroespasmo/diagnóstico , Trastornos Distónicos/diagnóstico , Músculos Faciales , Humanos , MasculinoRESUMEN
Mutations in the gene encoding amyloid precursor protein (APP) cause autosomal dominant inherited Alzheimer's disease (AD). We present a case of a 68-year-old female who presented with epileptic seizures, neuropsychiatric symptoms and progressive memory decline and was found to carry a novel APP variant, c.2062T>G pLeu688Val. A comprehensive literature review of all reported cases of AD due to APP mutations was performed in PubMed and Web of Science databases. We reviewed 98 studies with a total of 385 cases. The mean age of disease onset was 51.3 ± 8.3 (31-80 years). Mutations were most often located in exons 17 (80.8%) and 16 (12.2%). The most common symptoms were dementia, visuospatial symptoms, aphasia, epilepsy and psychiatric symptoms. Mutations in the ß-amyloid region, and specifically exon 17, were associated with high pathogenicity and a younger age of disease onset. We describe the second reported APP mutation in the Greek population. APP mutations may act variably on disease expression and their phenotype is heterogeneous.
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Enfermedad de Alzheimer/genética , Amnesia/genética , Precursor de Proteína beta-Amiloide/genética , Mutación Puntual , Trastornos Psicóticos/genética , Convulsiones/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Sustitución de Aminoácidos , Amnesia/complicaciones , Amnesia/diagnóstico por imagen , Amnesia/patología , Exones , Femenino , Expresión Génica , Grecia , Humanos , Masculino , Persona de Mediana Edad , Neuroimagen/métodos , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/patología , Convulsiones/complicaciones , Convulsiones/diagnóstico por imagen , Convulsiones/patologíaRESUMEN
BACKGROUND: Helicobacter pylori (H pylori) is a Gram-negative bacterium, considered to trigger autoimmune gastrointestinal disorders. This pathogen has also been linked to the autoimmune sequelae in extra-gastrointestinal diseases and peripheral neuropathies. Guillain-Barré syndrome (GBS) is a serious autoimmune demyelinating disorder of peripheral nerves, usually with a post-infectious onset. About 30% of cases of GBS attributed to by Campylobacter jejuni, so, H pylori, could be also involved. Growing evidence suggests the likely involvement of H pylori infection in the development of GBS. The aim of the current study was to therefore estimate the prevalence of H pylori antibodies in GBS. METHODS: A search of the literature was performed, using the PUBMED database, until December 2018. Data were extracted from six case-control studies, and a stratification analysis was conducted according to cerebrospinal fluid (CSF) or serum detection material. RESULTS: Among 29 records found, 6 studies met in the inclusion criteria for the meta-analysis. In the CSF subgroup, 105 participants were involved (40 GBS patients and 65 controls), while the serum subgroup included 325 participants (152 GBS and 173 controls). Data were combined using a fixed-effects model. Anti-H pylori IgG were significantly more prevalent in GBS patients compared to controls, in both CSF (95% CI: 9.66-186.56, OR: 42.45, Pz < .00001) and serum (95% CI: 1.30-4.11, OR: 2.31, Pz: .004) subgroups. CONCLUSION: The present meta-analysis showed a strong association between GBS and the presence of H pylori antibodies, especially in CSF, thereby suggesting a role of H pylori infection in the pathophysiology of GBS.
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Anticuerpos Antibacterianos/inmunología , Síndrome de Guillain-Barré/epidemiología , Infecciones por Helicobacter/epidemiología , Inmunoglobulina G/inmunología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/líquido cefalorraquídeo , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeoRESUMEN
OBJECTIVE: The objective of this study was to validate the recently updated research criteria for prodromal Parkinson's disease (pPD) proposed by the International Parkinson's Disease and Movement Disorders Society. METHODS: A total of 16 of 21 markers of pPD were ascertained in the Hellenic Longitudinal Investigation of Aging and Diet cohort composed of community-dwelling individuals aged ≥65 years. The probability of pPD was calculated for 961 individuals without Parkinson's disease (PD) or dementia with Lewy bodies at baseline who were followed-up for a median of 3 years. The ability of the criteria to predict conversion to PD/dementia with Lewy bodies was assessed by estimating their sensitivity and specificity, plotting receiver operating characteristics curves, and using logistic regression. These analyses were repeated using the original criteria. RESULTS: No incident PD/dementia with Lewy bodies case had probable pPD at baseline (ie, ≥80% pPD probability). At cut-offs of 10%, 30%, and 50% probability of pPD, the sensitivity and specificity of the criteria ranged from 4.5% to 27.3%, and 85.7% to 98.3% respectively. The area under the receiver operating characteristics curve was 0.691 (95% confidence intervals, 0.605-0.777). In logistic regression models, the criteria-derived posttest odds of pPD were a significant predictor of conversion at follow-up. The updated criteria performed similarly to the original but showed a slight increase in sensitivity. CONCLUSIONS: The new criteria demonstrated suboptimal sensitivity in our random sample of community-dwelling individuals. The absence of specialized assessments with high likelihood ratios in our cohort could be hindering the demonstration of higher sensitivities. Such assessments should be a part of future validation attempts. © 2020 International Parkinson and Movement Disorder Society.
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Enfermedad de Alzheimer , Enfermedad de Parkinson , Anciano , Estudios de Cohortes , Humanos , Enfermedad de Parkinson/diagnóstico , Síntomas Prodrómicos , Estudios ProspectivosRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder, caused by, so far, unknown pathogenetic mechanisms. There is no doubt that pro-inflammatory immune-mediated mechanisms are pivotal to the pathogenicity and progression of the disease. In this review, we highlight the binary role of microglia activation in the pathophysiology of the disorder, both neuroprotective and neuromodulatory. We present how the expression of several cytokines implicated in dopaminergic neurons (DA) degeneration could be used as biomarkers for PD. Viral infections have been studied and correlated to the disease progression, usually operating as trigger factors for the inflammatory process. The gut-brain axis and the possible contribution of the peripheral bowel inflammation to neuronal death, mainly dopaminergic neurons, seems to be a main contributor of brain neuroinflammation. The role of the immune system has also been analyzed implicating a-synuclein in the activation of innate and adaptive immunity. We also discuss therapeutic approaches concerning PD and neuroinflammation, which have been studied in experimental and in vitro models and data stemming from epidemiological studies.
Asunto(s)
Enfermedad de Parkinson/etiología , Animales , Autoinmunidad , Biomarcadores/metabolismo , Citocinas/inmunología , Citocinas/fisiología , Neuronas Dopaminérgicas/inmunología , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/fisiología , Humanos , Inflamación/inmunología , Inflamación/patología , Inflamación/fisiopatología , Microglía/inmunología , Microglía/fisiología , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/etiología , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Transducción de Señal , Virosis/complicaciones , alfa-Sinucleína/inmunología , alfa-Sinucleína/fisiologíaRESUMEN
Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS-associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population-based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population-based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease-modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis.
Asunto(s)
Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/etiología , Biomarcadores , Susceptibilidad a Enfermedades , Técnicas de Diagnóstico Molecular , Esclerosis Amiotrófica Lateral/metabolismo , Genes Modificadores , Predisposición Genética a la Enfermedad , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/tendencias , Mutación , Proteómica/métodosRESUMEN
BACKGROUND: The International Parkinson and Movement Disorder Society recently introduced a methodology for probability score calculation for prodromal PD. OBJECTIVES: To assess the probability of prodromal PD in an older population and investigate its possible association with Mediterranean diet adherence. METHODS: Data from a population-based cohort study of older adults (HEllenic Longitudinal Investigation of Aging and Diet) in Greece were used. Probability of prodromal PD was calculated according to International Parkinson and Movement Disorder Society research criteria. A detailed food frequency questionnaire was used to evaluate dietary intake and calculate Mediterranean diet adherence score, ranging from 0 to 55, with higher scores indicating higher adherence. RESULTS: Median probability of prodromal PD was 1.9%, ranging from 0.2 to 96.7% in 1,731 PD-free individuals aged ≥ 65 (41% male). Lower probability for prodromal PD (P < 0.001) in the higher Mediterranean diet adherence groups was noted, driven mostly by nonmotor markers of prodromal PD, depression, constipation, urinary dysfunction, and daytime somnolence. Each unit increase in Mediterranean diet score was associated with a 2% decreased probability for prodromal PD (P < 0.001). Compared to participants in the lowest quartile of Mediterranean diet adherence, those in the highest quartile were associated with a â¼21% lower probability for prodromal PD. CONCLUSIONS: Adherence to the Mediterranean diet is associated with lower probability of prodromal PD in older people. Further studies are needed to elucidate the potential causality of this association, potential relation of the Mediterranean diet to delayed onset or lower incidence of PD, as well as the underlying neurobiological mechanisms. © 2018 International Parkinson and Movement Disorder Society.