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1.
Neurol Sci ; 45(3): 1017-1030, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37721571

RESUMO

OBJECTIVE: In this systematic review and meta-analysis, we critically evaluate available evidence regarding the association between primary headaches and subsequent decline of cognitive function and dementia. BACKGROUND: Recent studies suggested that headache disorders may increase the risk for dementia. However, available studies are conflicting. METHODS: To identify qualifying studies, we searched scientific databases, including Pubmed, Scopus, Web of Science, Science Direct and BMC, screening for relevant papers. In order to reduce the heterogeneity between different studies, the analyses were further subdivided according to the clinical diagnoses and the study methodologies. RESULTS: We identified 23 studies investigating the association between primary headaches and the risk of dementia. Of these, 18 met our inclusion criteria for meta-analysis (covering 924.140 individuals). Overall effect-size shows that primary headaches were associated with a small increase in dementia risk (OR = 1,15; CI 95%: 1,03-1,28; p = 0,02). Analyzing subgroups, we found that migraine was associated with both a moderate increased risk of all-cause dementia (OR = 1,26; p = 0,00; 95% CI: 1,13-1,40) as well as a moderate increased risk of Alzheimer's disease (OR = 2,00; p = 0,00; 95% CI: 1,46-2,75). This association was significant in both case-control and retrospective cohort studies but not in prospective studies. CONCLUSIONS: Our study supports the presence of a link between primary headaches and dementia. However, in the subgroup analysis, only patients with migraine showed a moderate increase risk for all-cause dementia and for Alzheimer's disease. Additional rigorous studies are needed to elucidate the possible role of primary headaches on the risk of developing cognitive impairment and dementia.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Transtornos de Enxaqueca , Humanos , Doença de Alzheimer/complicações , Estudos Retrospectivos , Estudos Prospectivos , Cefaleia/epidemiologia , Cefaleia/complicações , Disfunção Cognitiva/complicações , Fatores de Risco , Transtornos de Enxaqueca/complicações
2.
Neurol Sci ; 45(6): 2877-2880, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38494459

RESUMO

BACKGROUND: Spinocerebellar ataxia 17 (SCA17) is a rare autosomal dominant form of inherited ataxia, caused by heterozygous trinucleotide repeat expansions encoding glutamine in the TATA box-binding protein (TBP) gene. CASE DESCRIPTION: We describe the clinical history, neuropsychological, and neuroimaging findings of a 42-year-old patient who presented for medical attention showing prevalent behavioral and cognitive problems along with progressively worsening gait disturbances. The patient's family history indicated the presence of SCA17 in the maternal lineage. Genetic analysis confirmed a heterozygous 52-CAG pathological expansion repeat in TBP (normal interval, 25-40 CAG. Brain 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed bilateral hypometabolism in the sensorimotor cortex, with a slight predominance on the right, as well as in the striatal nuclei and thalamic hypermetabolism, a finding similar to what is observed in Huntington's disease. The patient also underwent neuropsychological evaluation, which revealed mild cognitive impairment and difficulties in social interaction and understanding other's emotions (Faux Pas Test and Reading the Mind in the Eyes Test). CONCLUSION: Our report emphasizes the importance of considering SCA17 as a possible diagnosis in patients with a prevalent progressive cognitive and behavioral disorders, even with a pattern of FDG-PET hypometabolism not primarily indicative of this disease.


Assuntos
Disfunção Cognitiva , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Ataxias Espinocerebelares , Adulto , Humanos , Encéfalo/diagnóstico por imagem , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/genética , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/etiologia , Testes Neuropsicológicos , Transtornos do Comportamento Social/diagnóstico por imagem , Transtornos do Comportamento Social/etiologia , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Proteína de Ligação a TATA-Box/genética
3.
Neurol Sci ; 44(10): 3577-3585, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37199875

RESUMO

BACKGROUND: Heart failure (HF) is the second most important cardiac risk factor for stroke after atrial fibrillation (AF). Few data are available on mechanical thrombectomy (MT) in acute ischemic stroke (AIS) patients with HF. METHODS: The source of data is the multicentre Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS). All AIS patients ≥ 18 years receiving MT were categorised in two groups: HF and no-HF. Baseline clinical and neuroradiological findings on admission were analysed. RESULTS: Of 8924 patients, 642 (7.2%) had HF. Compared to the no-HF group, HF patients had higher prevalence of cardiovascular risk factors. Rate of complete recanalisation (TICI 2b-3) was 76.9% in HF vs 78.1% in no-HF group (p = 0.481). Rate of symptomatic intracerebral haemorrhage at 24-h non-contrast computed tomography (NCCT) was 7.6% in HF vs 8.3% in no-HF patients (p = 0.520). At 3 months, 36.4% of HF patients and 48.2% of no-HF patients (p < 0.001) had mRS 0-2, and mortality was, respectively, 30.7% and 18.5% (p < 0.001). In multivariate logistic regression, HF was independently associated with mortality at 3 months (OR 1.53, 1.24-1.88 95% CI, p < 0.001). In multivariate ordinal regression, HF patients had a probability of transitioning to a higher mRS level of 1.23 (1.05-1.44 95% CI, p = 0.012). The propensity score analysis of two groups matched for age, sex, and NIHSS at admission yielded the same results. CONCLUSION: MT is safe and effective in HF patients with AIS. Patients with HF and AIS suffered from higher 3-month mortality and unfavourable outcome regardless of acute treatments.


Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , Insuficiência Cardíaca , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/etiologia , Trombectomia/efeitos adversos , Resultado do Tratamento , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/cirurgia , Insuficiência Cardíaca/complicações , Sistema de Registros , Estudos Retrospectivos , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/epidemiologia , Procedimentos Endovasculares/efeitos adversos
4.
Neurol Sci ; 43(1): 275-284, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33942173

RESUMO

BACKGROUND: Dementia has devastating consequences for families with important physical, psychological, social, and financial effects. Evaluation of caregiver's needs may be an important step to reduce the burden of family caregivers of dementia patients. An Austrian scale, the Carers' Needs Assessment for Dementia, is now available for measuring the caregiver's needs. The aim of our study was to evaluate the psychometric properties of the Italian version of the CNA-D (iCNA-D). METHODS: A sample of 214 voluntary caregivers of dementia patients was recruited at the Department of Neuroscience, University of Turin (Italy). All participants were administered the iCNA-D. Validity and reliability of the instrument were evaluated using Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Symptom Checklist-90 (SCL-90), and the Italian version of Zarit Burden Interview (I-ZBI). RESULTS: The most common unmet need reported for the iCNA-D was "counseling and emotional support" (31.5%). This item demonstrates adequate reliability with moderate internal consistency for all "summary scores" of iCNA-D (α ≥ 0.75) and split-half correlation of more than 0.80 for two of them. We also found positive correlations in two out of three "summary scores" of iCNA-D and in the overall outcomes of BDI, BAI, SCL-90, and I-ZBI. CONCLUSIONS: The iCNA-D could be a valid and reliable tool for a comprehensive assessment of needs and possible social supports proposed to relatives who take care of patients with dementia. Better understanding of family caregivers' needs could improve planning of local services and reduce caregivers' perception of distress and burden.


Assuntos
Cuidadores , Demência , Demência/diagnóstico , Humanos , Avaliação das Necessidades , Reprodutibilidade dos Testes , Inquéritos e Questionários
5.
Neurol Sci ; 43(1): 313-317, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33904007

RESUMO

Orexins are hypothalamic neuropeptides that regulate several physiological functions, such as appetite, arousal, cognition, stress, sleep and metabolism. Emerging pieces of evidence suggest an orexinergic dysfunction in several neuropsychiatric disorders, including depression, anxiety and addiction. A syndromic overlap between behavioural variant frontotemporal dementia (bvFTD) and several psychiatric disorders was recently demonstrated. Therefore, we analysed cerebrospinal fluid (CSF) orexin A concentrations of 40 bvFTD and 32 non-demented patients, correlating neuropeptide concentrations with several clinical characteristics. A significant increase of orexin A concentrations was found in bvFTD patients when compared to controls (p<0.001). CSF orexin A concentration showed a correlation with Mini-Mental State Examination scores, drug assumption, history of compulsive behaviour and extrapyramidal signs. Moreover, we found a relationship between CSF markers of neurodegeneration, total tau and Aß1-42 and CSF orexin A concentrations. Our study provides evidence of an orexinergic dysfunction in bvFTD, correlating with several clinical symptoms. Further larger studies are needed to confirm our data.


Assuntos
Demência Frontotemporal , Orexinas/líquido cefalorraquidiano , Estudos de Casos e Controles , Demência Frontotemporal/líquido cefalorraquidiano , Humanos
6.
Int J Mol Sci ; 24(1)2022 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-36614097

RESUMO

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a key role in the understanding of such a diverse response. In order to investigate whether functional polymorphisms in proinflammatory cytokine genes (IL-1α, IL-1ß, IL-1RN; IL-6 and TNF-α) may influence the response to acute treatment, 313 consecutive patients with episodic migraine without aura were enrolled. Pain relief by administration of NSAIDs or triptans for three consecutive migraine attacks was evaluated. We found a significant association between A allele of the TNF-α promoter (−308 A/G) and a lack of efficacy after NSAID administration (p < 0.01, OR 2.51, 95% CI: 1.33 < OR < 4.75 compared to the G allele). Remaining polymorphisms had no significant effect on pain relief. Our study showed that a functional polymorphism in the TNF-α gene significantly modulates the clinical response to NSAID administration in acute attacks. Patients with higher production of the active cytokine during stress showed a significantly lower anti-migraine effect. Our results further support a role for TNF-α in the pathophysiological mechanisms of migraine attack.


Assuntos
Anti-Inflamatórios não Esteroides , Transtornos de Enxaqueca , Triptaminas , Humanos , Anti-Inflamatórios não Esteroides/uso terapêutico , Cefaleia/tratamento farmacológico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/genética , Triptaminas/uso terapêutico , Fator de Necrose Tumoral alfa/genética
7.
Neurol Sci ; 42(8): 3079-3081, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34021438

RESUMO

BACKGROUND: Headache is a frequent symptom of the novel coronavirus 19 disease (COVID-19). To date, there are limited information on how COVID-19 affects migraine and its treatment. CASE DESCRIPTION: A 47-year-old patient, suffering from chronic migraine and medication-overuse headache, in September 2020 started erenumab at 70 mg once monthly. Two months later, monthly migraine days decreased from 20 to 5. On the third month, the patient developed mild COVID-19 symptoms, experiencing extreme fatigue, hyposmia, and attention deficit, resulting positive for SARS-Cov-2 RNA. A significant increase in migraine attacks frequency was reported. Brain MRI and EEG were normal. Erenumab was increased to 140 mg/month, and attacks decreased to 3 monthly migraine days and remained stable. All the headaches experienced by our patient during the infection fulfilled the criteria of the migraine attacks, without tensive-like features. CONCLUSION: We report the first case showing the effects of SARS-CoV-2 infection in a patient with chronic migraine and medication-overuse headache treated with erenumab. Our case description suggests that inflammatory processes induced by SARS-CoV-2 infection may increase the frequency of migraine attacks, probably through an activation of the trigeminovascular system. Whether treatment with CGRP receptor antagonist may influence COVID is still debated. Additional studies regarding anti-CGRP monoclonal antibodies in COVID-19 patients are warranted.


Assuntos
COVID-19 , Transtornos de Enxaqueca , Anticorpos Monoclonais Humanizados , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Humanos , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , RNA Viral , SARS-CoV-2
8.
J Hum Genet ; 64(11): 1083-1090, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31501477

RESUMO

Primary familial brain calcification (PFBC) is a rare disease characterized by brain calcifications that mainly affect the basal ganglia, thalamus, and cerebellum. Among the four autosomal-dominant genes known to be associated with the disease, SLC20A2 pathogenic variants are the most common, accounting for up to 40% of PFBC dominant cases; variants include both point mutations, small insertions/deletions and intragenic deletions. Over the last 7 years, we have collected a group of 50 clinically diagnosed PFBC patients, who were screened for single nucleotide changes and small insertions/deletions in SLC20A2 by Sanger sequencing. We found seven pathogenic/likely pathogenic variants: four were previously described by our group, and three are reported here (c.303delG, c.21delG, and c.1795-1G>A). We developed and validated a synthetic Multiplex Ligation-dependent Probe Amplification (MLPA) assay for SLC20A2 deletions, covering all ten coding exons and the 5' UTR (SLC20A2-MLPA). Using this method, we screened a group of 43 PFBC-patients negative for point mutations and small insertions/deletions, and identified two novel intragenic deletions encompassing exon 6 NC_000008.10:g.(42297172_42302163)_(423022281_42317413)del, and exons 7-11 including the 3'UTR NC_000008.10:g.(?_42275320)_(42297172_42302163)del. Overall, SLC20A2 deletions may be highly underestimated PFBC cases, and we suggest MLPA should be included in the routine molecular test for PFBC diagnosis.


Assuntos
Encefalopatias/genética , Calcinose/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Adulto , Encéfalo/fisiopatologia , Encefalopatias/fisiopatologia , Calcinose/fisiopatologia , Éxons/genética , Humanos , Masculino , Linhagem , Mutação Puntual/genética , Polimorfismo de Nucleotídeo Único/genética , Deleção de Sequência/genética
9.
Cephalalgia ; 39(1): 15-20, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29682977

RESUMO

BACKGROUND: Recent studies suggested a potential association between both overt and subclinical hypothyroidism and migraine. Aims of this study were to estimate the comorbidity of migraine in patients with subclinical hypothyroidism and to evaluate associated clinical characteristics. METHODS: Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. RESULTS: The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs. 13%, p < 0.001; OR 5.80; 95% CI = 3.35-10.34). Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls ( p < 0.001 and p = 0.010, respectively). Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine. Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine ( p = 0.005). CONCLUSIONS: Our data suggest that migraine is more frequent in patients with subclinical hypothyroidism in respect to controls. Further studies are needed in order to confirm this association.


Assuntos
Hipotireoidismo/epidemiologia , Transtornos de Enxaqueca/epidemiologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência
12.
Int Psychogeriatr ; 30(12): 1871-1881, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29789032

RESUMO

ABSTRACTSince baseline executive dysfunction predicts worsening Instrumental Activities of Daily Living (i-ADL) over time and progression to Alzheimer's Disease (AD), we aimed to analyze the role of neuropsychological variables to outline which factors can contribute to functional impairment. Specific attention to executive functions (EFs) has been given.A total of 144 subjects complaining of different cognitive deficits - ranging from "MCI likely due to AD" to "mild AD patients" - underwent an overall neuropsychological assessment. The Behavioral Assessment of the Dysexecutive Syndrome was used to analyze EFs. We conducted multiple linear regression analyses to study whether the level of independent living skills - assessed with the Lawton-scale - could be associated with cognitive and behavioral measurements.We found a significant association between i-ADL and specific EFs measured by Rule Shift Cards (p = 0.04) and Modified Six Elements (p = 0.02). Moreover, considering i-ADL scores, we observed an involvement of mood changes and a reduced awareness of deficits in terms of Hamilton Depression Rating Scale (p = 0.02) and Awareness of Deficit Questionnaire - Dementia scale (p < 0.0001), respectively.Our results suggest the importance of considering the association between a reduction in i-ADL and executive dysfunction in patients who have AD etiopathology, for which the ability to inhibit a response, self-monitoring, set-shifting and mood deflection play a key role. Besides, no straightforward associations between i-ADL scores and global cognition, memory, language comprehension, attention, and perspective taking abilities were found.


Assuntos
Atividades Cotidianas/psicologia , Disfunção Cognitiva/diagnóstico , Função Executiva/fisiologia , Transtornos do Humor/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Disfunção Cognitiva/psicologia , Feminino , Humanos , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Transtornos Neurocognitivos/diagnóstico
13.
Curr Pain Headache Rep ; 22(5): 36, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29619630

RESUMO

PURPOSE OF THE REVIEW: The goals of this review are to evaluate recent studies regarding comorbidity between migraine and different metabolic and endocrine disorders and to discuss the role of insulin resistance as a common pathogenetic mechanism of these diseases. RECENT FINDINGS: Recently, several studies showed that migraine is associated with insulin resistance, a condition in which a normal amount of insulin induces a suboptimal physiological response. All the clinical studies that used the oral glucose tolerance test to examine insulin sensitivity found that, after glucose load, there is in migraine patients a significant increase of both plasmatic insulin and glucose concentrations in comparison with controls. On the contrary, no association was found between migraine and type 2 diabetes, while type 1 diabetes seems to have a protective effect in the disease. Obesity and hypertension were shown to be risk factors for both episodic and chronic migraine. Metabolic syndrome has been recently associated mainly with migraine with aura and is now considered a risk factor also for medication overuse headache. Finally, a bidirectional association between migraine and hypothyroidism has been recently demonstrated, suggesting that common genetic or autoimmune mechanisms underlie both diseases. Recent studies showed that insulin receptor signaling and the related physiological responses are altered in migraine and may have a relevant pathogenic role in the disease. Further studies are warranted in order to better elucidate mechanisms underlying insulin resistance in migraine in order to develop new therapeutic strategies for this debilitating disease.


Assuntos
Doenças do Sistema Endócrino/complicações , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/fisiopatologia , Humanos
14.
Cephalalgia ; 37(11): 1067-1073, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27553954

RESUMO

Background and aims Adiponectin, leptin, and resistin are adipocyte-derived secretory factors involved in endothelial function, weight, inflammation, and insulin resistance. Recent studies suggested a role for adipokines in episodic migraine as mediators of inflammatory processes. The aim of this study was to investigate plasma concentrations of adiponectin, leptin, and resistin in patients with chronic migraine. Materials and methods Twenty-seven chronic migraineurs (20 females, 7 males; mean age 49.0 ± 9.0 yrs) and 37 healthy controls (23 females, 14 males; mean age 49.8 ± 15.0 yrs) were selected for the study. Fasting plasmatic levels of total adiponectin, leptin, and resistin were measured using ELISA kits during a pain-free period. Fasting glucose, insulin, total and HDL-cholesterol, triglycerides, and ESR were also determined. Results Serum levels of adiponectin and resistin were significantly increased in chronic migraineurs in comparison with controls ( p = 0.001 and p = 0.032, respectively). After correction for BMI, sex and age, leptin levels were significantly increased in chronic migraineurs ( p = 0.007). A positive correlation between leptin concentrations and both indices of insulin resistance and markers of inflammation was found. Discussion Our data suggest that adiponectin and resistin are altered in non-obese chronic migraineurs. Further studies are needed to elucidate the neurobiological mechanisms underlying adipokine dysfunction in migraine.


Assuntos
Adiponectina/sangue , Leptina/sangue , Transtornos de Enxaqueca/sangue , Resistina/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Transtornos da Cefaleia/sangue , Humanos , Masculino , Pessoa de Meia-Idade
15.
Hum Mol Genet ; 23(21): 5630-7, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24908669

RESUMO

The G4C2-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of the CpG-island (5'of the repeat) in DNA samples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation level was significantly higher in FTLD expansion carriers than non-carriers (P = 7.8E-13). Our results were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an allele with >50 repeats, and was not detected in non-carriers or individuals with an intermediate allele (22-43 repeats). As expected, the position/number of methylated CpGs was concordant between the sense and anti-sense DNA strand, suggesting that it is a stable epigenetic modification. Analysis of the combined ALS and FTLD datasets (82 expansion carriers) revealed that the degree of methylation of the entire CpG-island or contribution of specific CpGs (n = 26) is similar in both syndromes, with a trend towards a higher proportion of ALS patients with a high methylation level (P = 0.09). In conclusion, we demonstrated that hypermethylation of the CpG-island 5'of the G4C2-repeat is expansion-specific, but not syndrome-specific (ALS versus FTLD).


Assuntos
Ilhas de CpG , Metilação de DNA , Expansão das Repetições de DNA , Degeneração Lobar Frontotemporal/genética , Proteínas/genética , Idade de Início , Idoso , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72 , Conjuntos de Dados como Assunto , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA
16.
Acta Neuropathol ; 129(5): 715-27, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25716178

RESUMO

The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5' CpG-island near the G4C2-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the main site of methylation. To evaluate (G4C2)n -methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G4C2-expansion is generally methylated in unrelated carriers of alleles >50 repeats (97 %), while small (<22 repeats) or intermediate (22-90 repeats) alleles were completely unmethylated. The presence of (G4C2)n -methylation does not separate the C9orf72-phenotypes (ALS vs. ALS/FTLD vs. FTLD), but has the potential to predict large vs. intermediate repeat length. Our results suggest that (G4C2)n -methylation might sometimes spread to the 5'-upstream region, but not vice versa. It is stable over time, since (G4C2)n -methylation was detected in carriers with a wide range of ages (24-74 years). It was identified in both blood and brain tissues for the same individual, implying its potential use as a biomarker. Furthermore, our findings may open up new perspectives for studying disease mechanisms, such as determining whether methylated and unmethylated repeats have the same ability to form a G-quadruplex configuration.


Assuntos
Esclerose Lateral Amiotrófica/genética , Ilhas de CpG , Metilação de DNA , Expansão das Repetições de DNA , Degeneração Lobar Frontotemporal/genética , Proteínas/genética , Idoso , Alelos , Proteína C9orf72 , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mapeamento por Restrição/métodos , Análise de Sequência de DNA
17.
Dement Geriatr Cogn Disord ; 38(3-4): 245-53, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24969517

RESUMO

BACKGROUNDS/AIMS: Alzheimer's disease (AD) is one of the main types of dementia affecting about 50-55% of all demented patients. Sleep disturbances in AD patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble the core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. The aim of our study was to investigate whether genetic variants in the hypocretin (HCRT) and in the hypocretin receptors 1 and 2 (HCRTR1, HCRTR2) genes could modify the occurrence and the clinical features of AD and to examine if these possible variants influence the role of the protein in sleep regulation. METHODS: Using a case-control strategy, we genotyped 388 AD patients and 272 controls for 10 SNPs in the HCRT, HCRTR1 and HCRTR2 genes. In order to evaluate which residues belong to the HCRTR2 binding site, we built a molecular model. RESULTS: The genotypic and allelic frequencies of the rs2653349 polymorphism were different (χ(2) = 5.77, p = 0.016; χ(2) = 6.728, p = 0.035) between AD patients and controls. The carriage of the G allele was associated with an increased AD risk (OR 2.53; 95% CI 1.10-5.80). No significant differences were found in the distribution of either genotypic or allelic frequencies between cases and controls in the HCRTR1 polymorphisms rs2271933, rs10914456 and rs4949449 and in the HCRTR2 polymorphism rs3122156. CONCLUSION: Our data support the hypothesis that the HCRTR2 gene is likely to be a risk factor for AD. The increased risk inferred is quite small, but in the context of a multi-factorial disease, the presence of this polymorphism may significantly contribute to influencing the susceptibility for AD by interacting with other unknown genetic or environmental factors in sleep regulation.


Assuntos
Doença de Alzheimer/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neuropeptídeos/genética , Receptores de Orexina/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Orexinas , Polimorfismo de Nucleotídeo Único
18.
Headache ; 54(9): 1515-22, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25324165

RESUMO

OBJECTIVES: To evaluate the prevalence of KCNK18 gene mutations in a dataset of Italian migraineurs, with and without aura, and in healthy controls, and to investigate in silico the functional effects of the mutations. BACKGROUND: A role for the KCNK18 gene encoding for TRESK, a member of the family of potassium channel, has been recently suggested in migraine with aura. METHODS: We sequenced the KCNK18 gene in 425 migraineurs (255 with aura and 170 without aura) and 247 healthy controls. RESULTS: Five genetic variants (R10G, C110R, Y163Y, S231P, and F372L) were found in 13 (5.1%) out of 255 migraine with aura patients, and 6 variants (R10G, D46D, C110R, Y163Y, S178T, and S231P) were identified in 12 (7.1%) out of 170 migraine without aura patients. In 2.8% of controls, the R10G and L20V substitutions were found. In silico analysis suggested that C110R, S178T, S231P, and F372L mutations may have potential damaging effect on channel function, whereas the remaining mutations may have low damaging effect. CONCLUSIONS: Our study shows the presence of several KCNK18 gene mutations in both migraine with aura and migraine without aura. However, the precise role of this gene in migraine predisposition deserves further studies.


Assuntos
Predisposição Genética para Doença/genética , Transtornos de Enxaqueca/genética , Canais de Potássio/genética , Adulto , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase
20.
Acta Neurochir (Wien) ; 155(8): 1511-5, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23728502

RESUMO

BACKGROUND: The exact pathophysiology of the development and rupture of saccular aneurysms is still controversial. Several lines of evidence indicate a role for inflammatory processes. Similarly, abnormal angiogenesis might be related to aneurysm growth. Expression of angiogenesis factors is higher in patients harboring aneurysms. The aim of this study was to verify the association of two functionally active polymorphisms (+ 396 C>T and 18 bp microdeletion) in the vascular endothelial growth factor (VEGF) gene with both susceptibility to and clinical features of aneurysmal subarachnoid hemorrhage (SAH) in an Italian population. METHOD: Allelic and genotypic frequencies of the + 396 C>T and the 18 bp microdeletion of the VEGF gene were determined in 200 patients and 200 healthy controls. RESULTS: Both allelic and genotypic frequencies of the examined polymorphisms in the VEGF gene were not significantly different between cases and controls. Furthermore, the different VEGF genotypes did not seem to significantly modify the main clinical features of the disease. CONCLUSIONS: Our data suggest that the VEGF gene is not a major genetic risk factor for aneurysmal subarachnoid hemorrhage.


Assuntos
Predisposição Genética para Doença , Aneurisma Intracraniano/genética , Polimorfismo Genético/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Feminino , Testes Genéticos/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
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