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1.
Am J Ophthalmol ; 246: 10-19, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35870490

RESUMO

PURPOSE: To evaluate the longitudinal changes of retinal neurodegeneration and choroidal thickness in diabetic patients with and without diabetic retinopathy (DR). DESIGN: Prospective observational cohort study. METHODS: This prospective observational cohort study recruited type 2 diabetic patients from a community registry in Guangzhou. All participants underwent annual ocular examinations via swept-source optical coherence tomography that obtained choroid thickness (CT), retinal thickness (RT), and ganglion cell-inner plexiform layer (GC-IPL) thickness. The changes in GC-IPL, CT, and RT between patients who developed incident DR (IDR) or remained non-DR (NDR) were compared during a 3-year follow-up. RESULTS: Among 924 patients, 159 (17.2%) patients developed IDR within the 3-year follow-up. A reduction in GC-IPL, RT, and CT was observed in NDR and IDR; however, CT thinning in patients with IDR was significantly accelerated, with an average CT reduction of -6.98 (95% CI: -8.26, -5.71) µm/y in patients with IDR and -3.98 (95% CI: -4.60, -3.36) µm/y in NDR patients (P < .001). Reductions in average GC-IPL thickness over 3 years were -0.97 (95% CI: -1.24, -0.70) µm/y in patients with IDR and -0.76 (95% CI: -0.82, -0.70) µm/y in NDR patients (P = .025). After adjusting for confounding factors, the average CT and GC-IPL thinning were significantly faster in patients with IDR compared with those who remained NDR by 2.09 µm/y (95% CI: 1.01, 3.16; P = .004) and -0.29 µm/y (95% CI: -0.49, -0.09; P = .004), respectively. The RT in the IDR group increased, whereas the RT in the NDR group decreased over time, with the adjusted difference of 2.09 µm/y (95% CI: 1.01, 3.16; P < .001) for central field RT. CONCLUSIONS: The rate of retinal neurodegeneration and CT thinning were significantly different between the eyes that developed IDR and remained NDR during the 3-year follow-up, but both groups observed thickness reduction. This indicates that GC-IPL and CTs may decrease before the clinical manifestations of DR.


Assuntos
Corioide , Diabetes Mellitus , Degeneração Neural , Neurônios Retinianos , Humanos , Corioide/diagnóstico por imagem , Corioide/patologia , Diabetes Mellitus/diagnóstico por imagem , Diabetes Mellitus/patologia , Retinopatia Diabética/epidemiologia , Estudos Prospectivos , Tomografia de Coerência Óptica , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/epidemiologia , Neurônios Retinianos/patologia
2.
Neurology ; 97(8): e836-e848, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34210821

RESUMO

OBJECTIVE: To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. METHODS: The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aß42/Aß40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders. RESULTS: There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: -0.061, 95% confidence interval: -0.089, -0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. CONCLUSION: In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.


Assuntos
Doença de Alzheimer/diagnóstico , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Disfunção Cognitiva/diagnóstico , Diabetes Mellitus/diagnóstico , Degeneração Neural/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores , Doenças de Pequenos Vasos Cerebrais/epidemiologia , Doenças de Pequenos Vasos Cerebrais/metabolismo , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Feminino , França/epidemiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Degeneração Neural/epidemiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons
3.
J Clin Neurosci ; 89: 336-342, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119290

RESUMO

Paraneoplastic neurological syndromes (PNS) are rare immune-mediated disorders, and the detection of onconeural antibodies is helpful for PNS diagnosis. The aim of this study was to investigate the clinical characteristics of patients with PNS with positive onconeural antibodies in a single center in Hubei, China. We retrospectively analyzed the clinical characteristics of 54 patients with positive onconeural antibodies from January 2016 to September 2020. Among 780 patients with suspected PNS, 54 (6.9%) had positive onconeural antibodies. Of those 54 patients, 28 (51.8%) were diagnosed with definite PNS and 13 (24.1%) with possible PNS. Eighteen (33.3%) patients were confirmed with cancer. Ten PNS syndromes were detected among the 28 patients with definite PNS, and they had either classical (12/28, 42.8%) or non-classical syndromes (17/28, 60.7%). Peripheral neuropathy (9/28, 32.1%), subacute cerebellar degeneration (4/28, 14.3%), and limbic encephalitis (4/28, 14.3%) were the most common PNS syndromes. The anti-CV2/CRMP5-antibody was observed most frequently. Lung cancer was the most common tumor type. For patients with possible PNS, peripheral neuropathy was the most common PNS syndrome, and the anti-Tr-antibody was the most frequent onconeural antibody. Immunotherapy was effective in treating PNS. The anti-CV2/CRMP5-antibody was the most subsequently observed antibody. The manifestations of PNS are diverse and include peripheral neuropathy, subacute cerebellar degeneration, and limbic encephalitis. In patients with PNS, lung cancer was the most common tumor.


Assuntos
Anticorpos/imunologia , Doenças Cerebelares/epidemiologia , Encefalite Límbica/epidemiologia , Neoplasias Pulmonares/epidemiologia , Degeneração Neural/epidemiologia , Síndromes Paraneoplásicas do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Paraneoplásicas do Sistema Nervoso/diagnóstico , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia
4.
Neurology ; 94(21): e2233-e2244, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32398359

RESUMO

OBJECTIVE: To compare different ß-amyloid (Aß), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies. METHODS: A total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aß42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation. RESULTS: Among CU participants, A-T-(N)- or A+T-(N)- variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures. CONCLUSIONS: Our findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.


Assuntos
Doença de Alzheimer/classificação , Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/epidemiologia , Degeneração Neural/epidemiologia , Proteínas tau/metabolismo , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina/metabolismo , Benzotiazóis/metabolismo , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Carbolinas/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência/estatística & dados numéricos , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Suécia/epidemiologia , Proteínas tau/líquido cefalorraquidiano
5.
Rev Med Interne ; 41(6): 404-412, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32165049

RESUMO

Calcifications of the basal ganglia are frequently seen on the cerebral CT scans and particularly in the globus pallidus. Their frequency increases physiologically with age after 50 years old. However, pathological processes can also be associated with calcium deposits in the gray nuclei, posterior fossa or white matter. Unilateral calcification is often related to an acquired origin whereas bilateral ones are mostly linked to an acquired or genetic origin that will be sought after eliminating a perturbation of phosphocalcic metabolism. In pathological contexts, these calcifications may be accompanied by neurological symptoms related to the underlying disease: Parkinson's syndrome, psychiatric and cognitive disorders, epilepsy or headache. The purpose of this article is to provide a diagnostic aid, in addition to clinical and biology, through the analysis of calcification topography and the study of different MRI sequences.


Assuntos
Doenças dos Gânglios da Base , Calcinose , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/patologia , Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/epidemiologia , Doenças dos Gânglios da Base/etiologia , Doenças dos Gânglios da Base/metabolismo , Calcinose/diagnóstico , Calcinose/epidemiologia , Calcinose/etiologia , Calcinose/metabolismo , Fosfatos de Cálcio/efeitos adversos , Fosfatos de Cálcio/metabolismo , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico , Degeneração Neural/epidemiologia , Degeneração Neural/etiologia , Degeneração Neural/metabolismo , Tomografia Computadorizada por Raios X
6.
Clin Genet ; 94(2): 246-251, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29652087

RESUMO

ZNF335 plays an essential role in neurogenesis and biallelic variants in ZNF335 have been identified as the cause of severe primary autosomal recessive microcephaly in 2 unrelated families. We describe, herein, 2 additional affected individuals with biallelic ZNF335 variants, 1 individual with a homozygous c.1399 T > C, p.(Cys467Arg) variant, and a second individual with compound heterozygous c.2171_2173delTCT, p.(Phe724del) and c.3998A > G, p.(Glu1333Gly) variants with the latter variant predicted to affect splicing. Whereas the first case presented with early death and a severe phenotype characterized by anterior agyria with prominent extra-axial spaces, absent basal ganglia, and hypoplasia of the brainstem and cerebellum, the second case had a milder clinical presentation with hypomyelination and otherwise preserved brain structures on MRI. Our findings expand the clinical spectrum of ZNF335-associated microcephaly.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Microcefalia/genética , Degeneração Neural/genética , Neurogênese/genética , Proteínas Nucleares/genética , Alelos , Processamento Alternativo/genética , Gânglios da Base/patologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Proteínas de Ligação a DNA , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/epidemiologia , Microcefalia/fisiopatologia , Mutação , Degeneração Neural/epidemiologia , Degeneração Neural/fisiopatologia , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição
7.
Presse Med ; 46(1): 79-84, 2017 Jan.
Artigo em Francês | MEDLINE | ID: mdl-27816346

RESUMO

Langerhans cell histiocytosis (LCH) is a rare multisystemic disease. LCH is characterized by proliferation of myeloid progenitors with altered differentiation program and similar phenotypic features to epidermal dendritic cells termed Langerhans cell. LCH cells express CD1a+ and langerin and exhibit BRAF V600E mutation in ∼50% of cases. Neurological involvement or neuro-LCH is observed in 5 to 10% of cases. Three subtypes of neuro-LCH are individualized. The tumor type, accounting for 45% of neuro-LCH, affect mainly young adults. Tumor neuro-LCH is characterized by space occupying lesion(s) with contrast enhancement on MRI. Clinical symptoms are due to tumor brain location(s). Pathological examination of tumor neuro-LCH lesions reveals typical features of LCH. Treatment relies on surgical resection with/without chemotherapy. Degenerative neuro-LCH, accounting for 45% of cases, is usually revealed, mostly in children, by: (i) a cerebellar syndrome, (ii) a pyramidal syndrome, (iii) a pseubulbar palsy, and/or (iv) cognitive disorders. On MRI, several signs may coexist: (i) cortex atrophy, (ii) white matter T2 hyperintensities, and (iii) deep gray matter T1 hyperintensities. Pathological analysis of degenerative neuro-LCH lesions have been rarely performed and have never detected CD1a+ histiocytes but unspecific lesions (i.e. gliosis, neuronal loss and/or demyelination). Treatment of degenerative neuro-LCH patients is poorly standardized and poorly efficient. Functional rehabilitation and socio-educational care of these young patients are crucial. The mixed subtype of neuro-LCH combines clinico-radio-pathological characteristics of the first two first forms in the same patient, and represents 10% of neuro-HL. Neuro-HL, therefore, includes three very distinct entities with epidemiological, clinical, radiological and histological specific features requiring specific medical management.


Assuntos
Encefalopatias , Histiocitose de Células de Langerhans , Adulto , Idade de Início , Encefalopatias/epidemiologia , Encefalopatias/etiologia , Encefalopatias/patologia , Criança , Pré-Escolar , Histiocitose de Células de Langerhans/classificação , Histiocitose de Células de Langerhans/complicações , Histiocitose de Células de Langerhans/epidemiologia , Histiocitose de Células de Langerhans/patologia , Humanos , Degeneração Neural/complicações , Degeneração Neural/epidemiologia , Degeneração Neural/patologia , Adulto Jovem
8.
Expert Opin Pharmacother ; 17(18): 2405-2415, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27785919

RESUMO

INTRODUCTION: Dopamine depletion is one of the most important features of Parkinson's Disease (PD). However, insufficient response to dopaminergic replacement therapy suggests the involvement of other neurotransmitter systems in the pathophysiology of PD. Cholinergic degeneration contributes to gait impairments, cognitive impairment, psychosis, and REM-sleep disturbances, among other symptoms. Areas covered: In this review, we explore the idea that enhancing cholinergic tone by pharmacological or neurosurgical procedures could be a first-line therapeutic strategy for the treatment of symptoms derived from cholinergic degeneration in PD. Expert opinion: Rivastigmine, a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase, is effective for dementia, whereas the use of Donepezil is still in the realm of investigation. Interesting results suggest the efficacy of these drugs in the treatment of gait dysfunction. Evidence on the clinical effects of these drugs for psychosis and REM-sleep disturbances is still weak. Stimulation of the pedunculo-pontine tegmental nuclei (which provide cholinergic innervation to the brain stem and subcortical nuclei) has also been used with some success for the treatment of gait dysfunction. Anticholinergic drugs should be used with caution in PD, as they may aggravate cholinergic symptoms. Notwithstanding, in some patients they might help control parkinsonian motor symptoms.


Assuntos
Colinérgicos/uso terapêutico , Neurônios Colinérgicos/patologia , Degeneração Neural/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Animais , Colinérgicos/farmacologia , Neurônios Colinérgicos/efeitos dos fármacos , Ensaios Clínicos como Assunto/métodos , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/epidemiologia , Demência/diagnóstico , Demência/dietoterapia , Demência/epidemiologia , Donepezila , Marcha/efeitos dos fármacos , Humanos , Indanos/farmacologia , Indanos/uso terapêutico , Degeneração Neural/diagnóstico , Degeneração Neural/epidemiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/epidemiologia
9.
J Neuroimaging ; 25(2): 289-295, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24716899

RESUMO

BACKGROUND AND PURPOSE: Hypertrophic olivary degeneration (HOD) is an uncommon type of transneuronal degeneration. Case reports and case series described in the literature provide a foundation of our current knowledge of HOD. These reports have described HOD most frequently to be unilateral and occurring in association with lesions in the dentato-rubro-olivary pathway. Our purpose was to evaluate the rate of bilateral versus unilateral HOD in a large case series. METHODS: A retrospective review was performed to identify patients in which the phrase "hypertrophic olivary degeneration" occurred in the radiology report. A diagnosis of HOD was confirmed on imaging if there was focal hyperintensity on T2-weighted images confined to either or both inferior olivary nuclei. RESULTS: A total of 102 patients had findings consistent with HOD. Of these, 76% had findings bilaterally. In 44%, a lesion could not be identified to explain HOD. Bilateral HOD was common in both lesional and nonlesional group, though more common in the nonlesional group. CONCLUSION: This study demonstrates that HOD is frequently bilateral. In slightly over 50% of patients with HOD, a lesion can be identified. In just under 50% patients with HOD, a lesion could not be identified and in these cases HOD was present bilaterally in the majority.


Assuntos
Degeneração Neural/epidemiologia , Degeneração Neural/patologia , Núcleo Olivar/patologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Humanos , Hipertrofia/epidemiologia , Hipertrofia/patologia , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Adulto Jovem
10.
Muscle Nerve ; 50(6): 956-61, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24647968

RESUMO

INTRODUCTION: Postural tachycardia syndrome (POTS) is a disorder of orthostatic intolerance characterized by excessive tachycardia of unknown etiology. Our objective in this study was to evaluate the correlation between C-fiber involvement as shown by skin biopsy and adrenergic cardiac metaiodobenzylguanadine (MIBG) uptake in POTS patients. METHODS: Skin biopsies of 84 patients with POTS were examined by Protein Gene Product 9.5 (PGP9.5) immunohistochemistry and were compared with MIBG myocardial scintigraphy imaging data. RESULTS: Mean intraepidermal nerve fiber (IENF) density was in the lower normal age-adjusted range, 7.2 ± 2.9/mm (normal ≥ 7/mm), and was slightly below the normal range in 45% of POTS patients. MIBG uptake was reduced in 21% of patients. Low IENF density correlated with reduced cardiac MIBG uptake (r = 0.39, P = 0.001). CONCLUSIONS: A subset of neuropathic POTS patients may harbor mild small fiber neuropathy with abnormalities of unmyelinated nerve fibers in the skin associated with reduced myocardial postganglionic sympathetic innervation.


Assuntos
Eritromelalgia/diagnóstico , Eritromelalgia/patologia , Coração/inervação , Degeneração Neural/diagnóstico , Degeneração Neural/patologia , Síndrome da Taquicardia Postural Ortostática/complicações , 3-Iodobenzilguanidina/metabolismo , Adolescente , Adulto , Biópsia , Estudos de Coortes , Comorbidade , Eritromelalgia/epidemiologia , Feminino , Coração/diagnóstico por imagem , Humanos , Incidência , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Degeneração Neural/epidemiologia , Fibras Nervosas Amielínicas/patologia , Síndrome da Taquicardia Postural Ortostática/patologia , Estudos Retrospectivos , Pele/inervação , Pele/patologia , Tomografia Computadorizada de Emissão de Fóton Único , Adulto Jovem
11.
Med Arch ; 68(3): 178-81, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25568528

RESUMO

BACKGROUND AND OBJECTIVES: Multiple Sclerosis (MS) is a chronic recurrent neurological disease that affects the Central Nervous System. This study aims to determine epidemiological factors that affect the appearance of MS, such as: incidence, prevalence, mortality, case appearance in accordance with the disease phase RRMS, SPMS, PPMS, gender, age, age group, and EDSS. MATERIALS AND METHODS: Deals with analyzing diagnosed and treated patients in the Clinic of Neurology in Prishtina during the period of 2003-2012. The research was conducted through a questionnaire applied in the diagnosed cases of MS. Information on patients was gathered from: history of illness, discharge reports and other relevant documents on MS illness. Clinical and epidemiological-descriptive study methods were used. The acquired results are shown through tables, graphics. Statistical processing was conducted with Microsoft Office Excel. RESULTS: From the total number of doubtful hospitalized cases of demyelinization (644) in the Clinic of Neurology in Prishtina, 412 cases (64%) were diagnosed with MS. For the period of 2003-2012 the prevalence of MS has been 19.6 of patients in 100,000 inhabitants. MS incidence rate was 0.95 of patients in 100,000 inhabitants. MS mortality rate was 0.14 of deceased in 100,000 inhabitants. The ratio female - male is 2.3:1. A larger number of patients fall within the age group of 30-39 years-old. Clinical form trends: RRSM 72.3%, SPSM 22.6%, PPSM 5.1%. The rate of EDSS 78.3% (0-3.5), 14.9% (4-6.5), 6.8% (7-9).


Assuntos
Esclerose Múltipla/epidemiologia , Esclerose Múltipla/fisiopatologia , Adulto , Distribuição por Idade , Idoso , Progressão da Doença , Feminino , Humanos , Incidência , Kosovo/epidemiologia , Masculino , Pessoa de Meia-Idade , Degeneração Neural/epidemiologia , Degeneração Neural/fisiopatologia , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Distribuição por Sexo , Inquéritos e Questionários , Taxa de Sobrevida , Adulto Jovem
12.
Exp Neurol ; 247: 25-38, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23542820

RESUMO

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by a progressive and extensive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and their terminals in the striatum, which results in debilitating movement disorders. This devastating disease affects over 1 million individuals in the United States and is increasing in incidence worldwide. Currently available pharmacological and surgical therapies ameliorate clinical symptoms in the early stages of disease, but they cannot stop or reverse degeneration of DA neurons. Stem cell therapies have come to the forefront of the PD research field as promising regenerative therapies. The majority of preclinical stem cell studies in experimental models of PD are focused on the idea that stem cell-derived DA neurons could be developed for replacement of diseased neurons. Alternatively, our studies and the studies from other groups suggest that stem cells also have the potential to protect and stimulate regeneration of compromised DA neurons. This review is focused on strategies based on the therapeutic potential for PD of the neurotrophic and neuroregenerative properties of a subclass of stem cells, mesenchymal stem cells (MSCs).


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Degeneração Neural/terapia , Doença de Parkinson/terapia , Animais , Humanos , Degeneração Neural/epidemiologia , Degeneração Neural/etiologia , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia
13.
Brain ; 136(Pt 2): 455-70, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23358603

RESUMO

Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A-D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe.


Assuntos
Proteínas de Ligação a DNA , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Neural/diagnóstico , Tratos Piramidais/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Proteínas de Ligação a DNA/imunologia , Feminino , Degeneração Lobar Frontotemporal/epidemiologia , Degeneração Lobar Frontotemporal/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/epidemiologia , Degeneração Neural/imunologia , Tratos Piramidais/imunologia
14.
Sleep Med ; 14(8): 763-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23058689

RESUMO

Since its original description, idiopathic rapid eye movement sleep behavior disorder (RBD) has become a well-established risk factor for neurodegenerative disease. Studies from sleep centers have found that at least 40-65% of patients with idiopathic RBD will develop a defined neurodegenerative phenotype over 10 years. This elevated risk of neurodegeneration has been recently confirmed in a population-based study of probable RBD. When a defined syndrome develops, it is almost always a 'synucleinopathy' (Parkinson's disease, Dementia with Lewy Bodies or multiple system atrophy). Often, manifestations of parkinsonism and cognitive impairment overlap. The ability of RBD to predict disease has major implications for development of neuroprotective therapy. First, RBD is a prodromal marker with a disease risk sufficiently high for design of neuroprotective trials. Second, study of idiopathic RBD allows prospective testing of other predictive markers of neurodegeneration. Third, it allows an unprecedented direct examination of the evolution of prodromal disease into defined neurodegenerative syndromes. This review summarizes what is known about the risk of neurodegeneration in idiopathic RBD, the utility of prodromal/predictive markers in synuclein-mediated neurodegeneration, and the evolution of motor and non-motor markers in prodromal stages.


Assuntos
Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Transtorno do Comportamento do Sono REM/patologia , Transtorno do Comportamento do Sono REM/fisiopatologia , Biomarcadores , Humanos , Degeneração Neural/epidemiologia , Doenças Neurodegenerativas/epidemiologia , Transtorno do Comportamento do Sono REM/epidemiologia , Fatores de Risco
15.
Brain ; 136(Pt 2): 483-93, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23114367

RESUMO

Spasticity is a common and disabling symptom observed in patients with central nervous system diseases, including amyotrophic lateral sclerosis, a disease affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, spasticity is traditionally thought to be the result of degeneration of the upper motor neurons in the cerebral cortex, although degeneration of other neuronal types, in particular serotonergic neurons, might also represent a cause of spasticity. We performed a pathology study in seven patients with amyotrophic lateral sclerosis and six control subjects and observed that central serotonergic neurons suffer from a degenerative process with prominent neuritic degeneration, and sometimes loss of cell bodies in patients with amyotrophic lateral sclerosis. Moreover, distal serotonergic projections to spinal cord motor neurons and hippocampus systematically degenerated in patients with amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and spinal cord before onset of motor symptoms. Furthermore, there was noticeable atrophy of serotonin neuronal cell bodies along with neuritic degeneration at disease onset. We hypothesized that degeneration of serotonergic neurons could underlie spasticity in amyotrophic lateral sclerosis and investigated this hypothesis in vivo using tail muscle spastic-like contractions in response to mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail muscle spastic-like contractions were observed at end-stage. Importantly, they were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at disease onset. In all, we show that serotonergic neurons degenerate during amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. Further research is needed to determine whether inverse agonists of 5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity in patients with amyotrophic lateral sclerosis.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Espasticidade Muscular/patologia , Degeneração Neural/patologia , Neurônios Serotoninérgicos/patologia , Adulto , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/epidemiologia , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Espasticidade Muscular/epidemiologia , Degeneração Neural/epidemiologia
16.
Mol Neurobiol ; 46(3): 614-38, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22899188

RESUMO

A growing body of epidemiologic and experimental data point to chronic bacterial and viral infections as possible risk factors for neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Infections of the central nervous system, especially those characterized by a chronic progressive course, may produce multiple damage in infected and neighbouring cells. The activation of inflammatory processes and host immune responses cause chronic damage resulting in alterations of neuronal function and viability, but different pathogens can also directly trigger neurotoxic pathways. Indeed, viral and microbial agents have been reported to produce molecular hallmarks of neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in synergy with other recognized risk factors, such as aging, concomitant metabolic diseases and the host's specific genetic signature. This review will focus on the contribution given to neurodegeneration by herpes simplex type-1, human immunodeficiency and influenza viruses, and by Chlamydia pneumoniae.


Assuntos
Degeneração Neural/microbiologia , Degeneração Neural/virologia , Animais , Infecções Bacterianas/epidemiologia , Sistema Nervoso Central/microbiologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Humanos , Modelos Biológicos , Degeneração Neural/epidemiologia , Degeneração Neural/patologia , Estresse Oxidativo , Viroses/epidemiologia
17.
J Neuroinflammation ; 9: 87, 2012 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-22559833

RESUMO

BACKGROUND: Neuroinflammation and protein accumulation are characteristic hallmarks of both normal aging and age-related neurodegenerative diseases. However, the relationship between these factors in neurodegenerative processes is poorly understood. We have previously shown that proteasome inhibition produced higher neurodegeneration in aged than in young rats, suggesting that other additional age-related events could be involved in neurodegeneration. We evaluated the role of lipopolysaccharide (LPS)-induced neuroinflammation as a potential synergic risk factor for hippocampal neurodegeneration induced by proteasome inhibition. METHODS: Young male Wistar rats were injected with 1 µL of saline or LPS (5 mg/mL) into the hippocampus to evaluate the effect of LPS-induced neuroinflammation on protein homeostasis. The synergic effect of LPS and proteasome inhibition was analyzed in young rats that first received 1 µL of LPS and 24 h later 1 µL (5 mg/mL) of the proteasome inhibitor lactacystin. Animals were sacrificed at different times post-injection and hippocampi isolated and processed for gene expression analysis by real-time polymerase chain reaction; protein expression analysis by western blots; proteasome activity by fluorescence spectroscopy; immunofluorescence analysis by confocal microscopy; and degeneration assay by Fluoro-Jade B staining. RESULTS: LPS injection produced the accumulation of ubiquitinated proteins in hippocampal neurons, increased expression of the E2 ubiquitin-conjugating enzyme UB2L6, decreased proteasome activity and increased immunoproteasome content. However, LPS injection was not sufficient to produce neurodegeneration. The combination of neuroinflammation and proteasome inhibition leads to higher neuronal accumulation of ubiquitinated proteins, predominant expression of pro-apoptotic markers and increased neurodegeneration, when compared with LPS or lactacystin (LT) injection alone. CONCLUSIONS: Our results identify neuroinflammation as a risk factor that increases susceptibility to neurodegeneration induced by proteasome inhibition. These results highlight the modulation of neuroinflammation as a mechanism for neuronal protection that could be relevant in situations where both factors are present, such as aging and neurodegenerative diseases.


Assuntos
Hipocampo/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Degeneração Neural/induzido quimicamente , Inibidores de Proteassoma/toxicidade , Acetilcisteína/análogos & derivados , Acetilcisteína/toxicidade , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Sinergismo Farmacológico , Hipocampo/enzimologia , Hipocampo/patologia , Inflamação/induzido quimicamente , Inflamação/epidemiologia , Inflamação/patologia , Masculino , Degeneração Neural/epidemiologia , Degeneração Neural/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Wistar , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/fisiologia
18.
J Neurol Sci ; 312(1-2): 102-7, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21872275

RESUMO

Fig4 null reduces phosphatidylinositol-3,5-diphosphate concentration and causes severe neuronal degeneration in both pale-tremor (plt) mice and patients with Charcot-Marie-Tooth disease type 4J (CMT4J), an inherited condition with recessive mutations in FIG4. Our previous study shows that minor trauma is associated with an accelerated course of motor neuron degeneration in patients with CMT4J. Heterozygous loss of FIG4 function has been suggested to be a risk factor in developing sporadic amyotrophic lateral sclerosis. We therefore hypothesize that minor trauma may trigger or exacerbate motor neuron degeneration in mice with fig4 haploinsufficiency (plt+/-). We have studied 18 wild-type and 18 plt+/- mice and created nerve injury by compressing the sciatic nerve. Outcomes in the mice were evaluated by nerve conduction study, Rotarod, and nerve morphology. No differences were found between wild-type and plt+/- mice. Taken together, our results demonstrate that haploinsufficiency of fig4 does not impose risks in rodents to develop neuronal degeneration in either naïve or traumatic conditions.


Assuntos
Flavoproteínas/genética , Degeneração Neural/genética , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/genética , Animais , Feminino , Flavoproteínas/metabolismo , Deleção de Genes , Haploinsuficiência/genética , Masculino , Camundongos , Camundongos Mutantes Neurológicos , Neurônios Motores/patologia , Neurônios Motores/fisiologia , Degeneração Neural/epidemiologia , Degeneração Neural/patologia , Condução Nervosa/genética , Fosfatases de Fosfoinositídeos , Fatores de Risco , Nervo Isquiático/patologia , Neuropatia Ciática/epidemiologia , Neuropatia Ciática/patologia
19.
J Neurol Sci ; 313(1-2): 22-6, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22014645

RESUMO

Recent randomized trials have shown that cilostazol is superior to aspirin for secondary stroke prevention. We hypothesized that combining cilostazol with aspirin is more effective than aspirin alone in patients with acute ischemic stroke. This randomized study compared the effects of oral aspirin alone to aspirin plus cilostazol in patients with non-cardioembolic ischemic stroke within 48 h of stroke onset. NIH Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores were checked before and after 14 days and 6 months of drug administration. The primary and secondary endpoints were neurological deterioration or stroke recurrence (NIHSS score ≥ 1) within 14 days and 6 months, respectively. For statistical analysis, on-treatment analysis was conducted. Seventy-six patients were enrolled in the study. The primary endpoint was significantly higher in the aspirin group than in the aspirin plus cilostazol group (28% vs. 6%, relative risk (RR): 0.21, 95% confidence intervals (CI): 0.05-0.87, p=0.013). Among the patients who did not reach these endpoints, the mean improvement in the NIHSS score at day 14 tended to be better (-1.8 ± 1.2 vs. -1.2 ± 1.0, p=0.078) and the frequency of the favorable functional status of mRS 0-1 at month 6 was significantly higher (RR: 1.48, 95% CI: 1.07-2.06, p=0.0048) in the aspirin plus cilostazol group than in the aspirin group. Patients treated with aspirin plus cilostazol during the acute phase of stroke had less neurological deterioration and more favorable functional status than those treated with aspirin alone.


Assuntos
Aspirina/administração & dosagem , Isquemia Encefálica/tratamento farmacológico , Degeneração Neural/prevenção & controle , Acidente Vascular Cerebral/tratamento farmacológico , Tetrazóis/administração & dosagem , Idoso , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/patologia , Cilostazol , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/epidemiologia , Degeneração Neural/patologia , Projetos Piloto , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/patologia , Fatores de Tempo , Resultado do Tratamento
20.
Exp Neurol ; 233(1): 79-86, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22001159

RESUMO

In this review, we focus on the relationship among Parkinson's disease (PD), stress and depression. Parkinson's disease patients have a high risk of developing depression, and it is possible that stress contributes to the development of both pathologies. Stress dysfunction may have a role in the etiology of preclinical non-motor symptoms of PD (such as depression) and, later in the course of the disease, may worsen motor symptoms. However, relatively few studies have examined stress or depression and the injured nigrostriatal system. This review discusses the effects of stress on neurodegeneration and depression, and their association with the symptoms and progression of PD.


Assuntos
Transtorno Depressivo/etiologia , Doença de Parkinson/etiologia , Estresse Psicológico/complicações , Animais , Corpo Estriado/patologia , Transtorno Depressivo/epidemiologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Degeneração Neural/epidemiologia , Degeneração Neural/etiologia , Degeneração Neural/patologia , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Estresse Psicológico/epidemiologia , Estresse Psicológico/patologia
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