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1.
Neurogenetics ; 15(1): 19-21, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24515844

RESUMO

Neurogenetic tests are increasingly requested by clinical neurologists without any formal training in clinical genetics. The aim of our study was to assess the documentation of consent and disclosure of genetic test results in a large regional clinical neuroscience centre. Documentation of some form of consent was evident in only 26/132 (20 %) of tests. However, the higher proportion of both positive and negative results disclosed (50/132, 38 %) suggest that the former figure may underestimate actual rates of undocumented consent within the clinical setting. Our findings highlight the need for a review of established practices surrounding consent in clinical neurology.


Assuntos
Revelação , Testes Genéticos/normas , Consentimento Livre e Esclarecido , Neurologia/normas , Documentação , Testes Genéticos/métodos , Humanos , Neurologia/métodos , Relações Médico-Paciente , Estudos Retrospectivos
2.
Bone ; 168: 116651, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36574893

RESUMO

The relative contributions of factors such as muscle strength, falls risk and low bone mineral density (BMD) to increased fracture risk in Parkinson's Disease (PD) were examined in an analysis of 5212 community-dwelling women age 75 years or more recruited to a randomised, double-blind, placebo-controlled study of the oral bisphosphonate, clodronate. Similar number of PD and non-PD subjects received treatment. Each participant had measurements of hip and forearm BMD, muscle strength (hand grip strength and maximum isometric quadriceps strength), ability in the sit-to-stand test, and postural stability. Incident radiographic and/or surgically verified fractures, and deaths, were recorded over an average follow-up of 3.8 years. A diagnosis of PD was made if it was self-reported and appropriate medication was recorded at the study entry. 47 of the women (0.9 %) had a diagnosis of PD at baseline. They were of similar age to those without PD, but reported higher disability scores and lower quality of life. While BMD at the forearm and hip regions was lower in PD, this only reached statistical significance at the femoral neck (0.61 ± 0.12 vs 0.65 ± 0.12 g/cm2, p = 0.037). Right hand grip strength was non-significantly lower in PD, but maximum right quadriceps strength was much reduced (96.9 ± 49.3 vs 126.3 ± 59.2 N, p = 0.003). Eleven (23.4 %) of the women with PD sustained 12 fractures, while 609 women (11.8 %) without PD sustained 742 osteoporotic fractures. The risk of osteoporotic fracture associated with PD was 2.24-fold higher in women with PD (Cox-regression HR 2.24, 95 % CI 1.23-4.06) and this remained high when adjusted for death as a competing risk (2.17, 95 % CI 1.17-4.01, p = 0.013). Following adjustment for femoral neck BMD, PD remained a significant predictor of fracture (HR 2.04, 1.12-3.70, p = 0.020). Entering PD as a risk variable using the rheumatoid arthritis input as a surrogate resulted in a reduction in PD as a FRAX-independent risk factor, particularly when BMD was included in FRAX (1.65, 95 % CI), but the relationship between PD and fracture risk appears to remain of clinical significance. The study suggests that PD may be an independent input in future iterations of FRAX, possibly due to non-skeletal components of risk such as reduced lower limb muscle strength. Introducing measures of muscle strength and performance in FRAX could also be considered.


Assuntos
Fraturas do Quadril , Fraturas por Osteoporose , Doença de Parkinson , Humanos , Feminino , Idoso , Densidade Óssea , Força da Mão , Doença de Parkinson/complicações , Qualidade de Vida , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Fatores de Risco , Medição de Risco , Fraturas do Quadril/complicações
3.
BMJ Open ; 10(8): e038911, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32759251

RESUMO

INTRODUCTION: There are no disease-modifying treatments for Parkinson's disease (PD). We undertook the first drug screen in PD patient tissue and idntified ursodeoxycholic acid (UDCA) as a promising mitochondrial rescue agent. The aims of this trial are to determine safety and tolerability of UDCA in PD at 30 mg/kg, confirm the target engagement of UDCA, apply a novel motion sensor-based approach to quantify disease progression objectively, and estimate the mean effect size and its variance on the change in motor severity. METHODS AND ANALYSIS: This is a phase II, two-centre, double-blind, randomised, placebo-controlled trial of UDCA at a dose of 30 mg/kg in 30 participants with early PD. Treatment duration is 48 weeks, followed by an 8-week washout phase. Randomisation is 2:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48 and 56. The primary outcome is safety and tolerability. Secondary outcomes will compare the change between baseline and week 48 using the following three approaches: the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part 3 in the practically defined 'OFF' medication state; confirmation of target engagement, applying 31Phosphorus MR Spectroscopy to assess the levels of ATP and relevant metabolites in the brain; and objective quantification of motor impairment, using a validated, motion sensor-based approach. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups. For each secondary outcome, the change from baseline will be summarised within treatment groups using summary statistics and appropriate statistical tests assessing for significant differences. All outcomes will use an intention-to-treat analysis population. ETHICS AND DISSEMINATION: This trial has been approved by the East of England - Cambridgeshire and Hertfordshire Research Ethics committee. Results will be disseminated in peer-reviewed journals, presentations at scientific meetings and to patients in a lay-summary format. TRIAL REGISTRATION NUMBER: NCT03840005.


Assuntos
Doença de Parkinson , Ácido Ursodesoxicólico , Progressão da Doença , Método Duplo-Cego , Inglaterra , Humanos , Doença de Parkinson/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico
4.
Eur J Neurol ; 15(7): 749-53, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18484991

RESUMO

BACKGROUND AND PURPOSE: The cause of Tourette syndrome (TS) is not precisely known, although several lines of evidence point at an involvement of the immune system in its pathogenesis. RESULTS: Here, we report the results of a pilot study investigating frequently analysed lymphocyte surface markers in 20 adult patients with TS (16 males; 37.3 +/- 15.8 years) and 20 matched controls (16 males; 37.5 +/- 15.3 years). Statistical analysis revealed significant differences for the investigated lymphocyte surface markers. The difference in CD69+/CD22+-B cells (23.0 +/- 10.5% vs. 13.1 +/- 6.1%; P = 0.001) and in CD95+/CD4+-T cells (41.5 +/- 12.1% vs. 24.6 +/- 10.0%; P = 0.0001) was still significant after Bonferroni-Holm correction. CONCLUSION: Our preliminary data indicate that TS may be associated with an increased peripheral immune activity.


Assuntos
Imunofenotipagem , Linfócitos/imunologia , Síndrome de Tourette/imunologia , Adulto , Idoso , Antígenos CD/metabolismo , Feminino , Citometria de Fluxo , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto
5.
Brain ; 128(Pt 8): 1855-60, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15947063

RESUMO

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.


Assuntos
Ataxia/genética , Síndrome do Cromossomo X Frágil/genética , Atrofia de Múltiplos Sistemas/genética , Tremor/genética , Idoso , Ataxia/complicações , Ataxia/diagnóstico , Ataxia Cerebelar/complicações , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/diagnóstico , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Mutação , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/genética , Proteínas de Ligação a RNA/genética , Sequências Repetitivas de Ácido Nucleico/genética , Tremor/complicações , Tremor/diagnóstico
6.
Neurosci Lett ; 630: 23-29, 2016 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-27412236

RESUMO

Mutations in parkin cause autosomal recessive Parkinsonism and mitochondrial defects. A recent drug screen identified a class of steroid-like hydrophobic compounds able to rescue mitochondrial function in parkin-mutant fibroblasts. Whilst these possess therapeutic potential, the size and high hydrophobicity of some may limit their ability to penetrate the blood-brain barrier from systemic circulation, something that could be improved by novel drug formulations. In the present study, the steroid-like compounds Ursolic Acid (UA) and Ursocholanic Acid (UCA) were successfully encapsulated within nanoscopic polymersomes formed by poly(2-(methacryloyloxy)ethyl phosphorylcholine)-poly(2-di-isopropylamino)ethyl methacrylate) (PMPC-PDPA) and separated into spherical and tubular morphologies to assess the effects of nanoparticle mediated delivery on drug efficacy. Following incubation with either morphology, parkin-mutant fibroblasts demonstrated time and concentration dependent increases in intracellular ATP levels, resembling those resulting from treatment with nascent UA and UCA formulated in 0.1% DMSO, as used in the original drug screen. Empty PMPC-PDPA polymersomes did not alter physiological measures related to mitochondrial function or induce cytotoxicity. In combination with other techniques such as ligand functionalisation, PMPC-PDPA nanoparticles of well-defined morphology may prove a promising platform for tailoring the pharmacokinetic profile and organ specific bio-distribution of highly hydrophobic compounds.


Assuntos
Ácidos Cólicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Fibroblastos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Nanocápsulas/administração & dosagem , Fosforilcolina/análogos & derivados , Ácidos Polimetacrílicos/farmacologia , Triterpenos/farmacologia , Ubiquitina-Proteína Ligases/genética , Trifosfato de Adenosina/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Mitocôndrias/metabolismo , Mutação , Nanocápsulas/toxicidade , Nanocápsulas/ultraestrutura , Fosforilcolina/farmacologia , Fosforilcolina/toxicidade , Ácidos Polimetacrílicos/toxicidade , Ácido Ursólico
7.
Neurology ; 49(6): 1598-604, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9409353

RESUMO

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown cause. The only case-control study conducted in MSA patients to date suggested a possible contributory genetic component in the pathogenesis of this disorder. The aim of this study was to evaluate a possible overlap between clinically or pathologically well-defined MSA and other conditions with an identified genetic defect causing spinocerebellar degeneration in humans or mutant mice strains. The spinocerebellar ataxia type 1 and 3 genes (SCA1 and SCA3) were analyzed for a pathologic expansion in 80 patients with MSA to evaluate a possible overlap between MSA and SCA1 or SCA3. Weaver mice and lurcher mice are animal models for spinocerebellar degeneration; both share pathologic features with MSA. We sequenced the H5 pore region of the human homologue of the weaver mouse gene, hiGIRK2, in all our patients. In lurcher mice, previous biochemical studies have shown a decreased intracellular response to insulin-like growth factor 1 (IGF-1) in the cerebellar cortex, and we thus investigated the possibility of an allelic association between MSA and the receptor for IGF-1. In addition, we evaluated a possible involvement of the ciliary neurotrophic factor gene (CNTF) and examined the role of HLA-A32 to clarify the conflicting data from previous studies. No changes were detected in any of the analyzed genes. Our studies strongly suggest that MSA is an autonomous syndrome distinct from identified genetic causes for spinocerebellar degeneration.


Assuntos
Atrofia de Múltiplos Sistemas/genética , Degenerações Espinocerebelares/genética , Alelos , Animais , Fator Neurotrófico Ciliar , Genótipo , Heterozigoto , Homozigoto , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Mutantes Neurológicos/genética , Mutação , Proteínas do Tecido Nervoso/genética , Receptores de Somatomedina/genética , Sequências Repetitivas de Ácido Nucleico , Homologia de Sequência do Ácido Nucleico
8.
Neuroscience ; 72(4): 877-9, 1996 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8735215

RESUMO

The pathological hallmark of Parkinson's disease is cell death of dopaminergic neurons in the substantia nigra, resulting in striatal dopaminergic deficit and a clinical syndrome dominated by disorders of movement. The cause for this cell loss is unknown, but the possibility of a contributing genetic factor is increasingly recognized. Homozygous weaver mice, a mutant mouse strain, display progressive postnatal depletion of dopaminergic cells in the mesencephalon and have thus been proposed as an animal model for Parkinson's disease. Recently, mGIRK2, a putative G-protein inward rectifier K+ channel, has been identified as the causative gene in the weaver mouse and a homozygous mutation has been described in the H5 pore region of this channel. The human homologue of mGIRK2, KCNJ7 or hiGIRK2, has previously been isolated on chromosome 21q22.1. A possible involvement of this gene in the pathogenesis of Parkinson's disease has been discussed. To evaluate the possibility of a shared genetic defect in weaver mouse and Parkinson's disease, we analysed the H5 pore region of hiGIRK2 in familial and sporadic cases of Parkinson's disease. The sequence was normal in all cases examined, suggesting a differing aetiology of nigral cell loss in Parkinson's disease and weaver mice.


Assuntos
Camundongos Mutantes Neurológicos/genética , Doença de Parkinson/genética , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Homologia de Sequência do Ácido Nucleico , Animais , Sequência de Bases , DNA/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Humanos , Camundongos , Dados de Sequência Molecular , Porinas/genética , Canais de Potássio/ultraestrutura
9.
J Neurol ; 244(4): 262-5, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9112596

RESUMO

To date, five single base pair changes of the mitochondrial DNA have been reported to occur either exclusively or with increased frequency in Caucasian patients with Parkinson's disease (PD) and it has been postulated that these mutations might be casually related to the observed inhibition of mitochondrial respiratory chain function in PD. To evaluate these findings, we analysed the frequency of all five polymorphisms in 100 cases of pathologically proven cases of PD. We were either unable to detect the previously described polymorphisms in our series or found them to be present with the same frequency among controls. Our data do not support the hypothesis of an involvement of the mitochondrial DNA in the pathogenesis of PD.


Assuntos
DNA Mitocondrial/metabolismo , Doença de Parkinson/genética , Polimorfismo Genético/genética , Adulto , Feminino , Humanos , Masculino , Doença de Parkinson/etiologia
10.
J Neurol Sci ; 141(1-2): 27-32, 1996 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-8880688

RESUMO

GTP cyclohydrolase I (GTPCH) has recently been identified as the first causative gene for Dopa-responsive dystonia (DRD). DRD typically presents with dystonia in the lower limbs in childhood, but may produce an akinetic-rigid syndrome in middle and old age. We have sequenced the GTPCH gene in 29 Parkinsonian patients without a positive family history for DRD, but who shared at least one feature of the akinetic-rigid presentation of DRD: 23 patients had at least one living relative who also suffered from an akinetic-rigid syndrome; 2 patients had an abnormally mild course of their parkinsonism which was extremely dopa-responsive. DNA was also analysed from 4 brain samples of patients who were clinically diagnosed as suffering from Parkinson's disease, but then did not show any pathological findings at post mortem. No changes in the sequence of the GTPCH gene were detected. We conclude that so far there is no evidence that mutations of the GTPCH gene are responsible for the development of parkinsonism in patients without a positive family history of DRD.


Assuntos
GTP Cicloidrolase/genética , Doença de Parkinson Secundária/genética , Idoso , Idoso de 80 Anos ou mais , Química Encefálica , Estudos de Avaliação como Assunto , Éxons/genética , Feminino , Humanos , Masculino , Mutação/fisiologia , Doença de Parkinson Secundária/enzimologia , Doença de Parkinson Secundária/mortalidade , Análise de Sequência de DNA
11.
J Neural Transm Suppl ; 56: 155-64, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10370909

RESUMO

Multiple system atrophy (MSA) is a degenerative central nervous system disease of unclear origin. Patients affected typically show symptoms attributable to the combined involvement of the extrapyramidal, pyramidal, cerebellar and autonomic nervous systems. At onset patients mostly see a doctor because of extrapyramidal or--more rarely--cerebellar symptoms. Evidence of autonomic nervous system involvement is often not apparent, at least to the neurologist, before the history is taken. In later stages, by contrast, involvement of all of the above systems is clinically detectable.


Assuntos
Atrofia de Múltiplos Sistemas/patologia , Humanos , Atrofia de Múltiplos Sistemas/etiologia , Sistema Nervoso/patologia
12.
J Neural Transm Suppl ; 46: 325-37, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8821069

RESUMO

The results of selected clinical research projects related to epidemiological, genetic, pharmacological, kinesiological, and neuroimaging aspects (SPECT, PET, MRI, functional MRI) of basal ganglia disorders such as Parkinson's disease, Progressive Supranuclear Palsy, Multiple System Atrophy and Wilson's disease are summarized. A retrospective pharmacoeconomic analysis of Parkinson's disease is presented. These studies are part of a nationwide research program of the German ministry of research and technology (BMFT) entitled "Parkinson's disease and other basal ganglia disorders" and were carried out at the Department of Neurology, LMU München.


Assuntos
Doenças dos Gânglios da Base/diagnóstico , Imageamento por Ressonância Magnética , Doença de Parkinson/diagnóstico , Tomografia Computadorizada de Emissão de Fóton Único , Doenças dos Gânglios da Base/tratamento farmacológico , Doenças dos Gânglios da Base/epidemiologia , Doenças dos Gânglios da Base/genética , Análise Custo-Benefício , Alemanha/epidemiologia , Humanos , Cinesiologia Aplicada , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Estudos Retrospectivos
13.
AJNR Am J Neuroradiol ; 31(5): 856-61, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20299428

RESUMO

BACKGROUND AND PURPOSE: Imaging studies have shown that children with NF-1 have increased brain volumes compared with age-matched controls and the CCs are disproportionately large. The purpose of this study was to determine if the CC in adults with NF-1 differed from that in matched controls by using DTI and volumetric imaging. MATERIALS AND METHODS: MR imaging with DTI was performed in 10 adults with NF-1 and in 10 age-, sex-, and handedness-matched controls by using a 3T system. Total brain volumes and the areas and central lengths of the CC were calculated, along with the radial width of callosal subdivisions, in the 2 groups. RESULTS: Our results showed that the total brain volume was not significantly different between adults with NF-1 and matched controls. The length and total cross-sectional area of the CC were statistically larger in adults with NF-1 compared with controls (approximately 10% longer and 20% greater area). On DTI we found a preservation of the primary eigenvalue with increases in the minor eigenvalues at the genu. CONCLUSIONS: We have shown that the increased size of the CC found in children with NF-1 is also present in adults with the syndrome, whereas no difference in total brain volume was found.


Assuntos
Corpo Caloso/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Neurofibromatose 1/diagnóstico , Adulto , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Neurology ; 67(12): 2250-2, 2006 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-17190957

RESUMO

We assessed seven patients with hereditary neuropathy with liability to pressure palsies (HNPP) with 16 electrophysiological tests and cranial MRI for CNS abnormalities. Mean latencies differed between patients with HNPP and controls for the blink reflex, the jaw-opening reflex, and acoustic evoked potentials. MRI abnormalities were observed in four patients. Our study suggests subclinical but functionally relevant CNS myelin damage in HNPP.


Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , Neuropatia Hereditária Motora e Sensorial/patologia , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Fibras Nervosas Mielinizadas/patologia , Paralisia/patologia , Paralisia/fisiopatologia , Adulto , Idoso , Eletroencefalografia , Potenciais Evocados , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
20.
J Neurol Neurosurg Psychiatry ; 76(8): 1058-63, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16024878

RESUMO

Parkinson's disease and Huntington's disease are both model diseases. Parkinson's disease is the most common of several akinetic-rigid syndromes and Huntington's disease is only one of an ever growing number of trinucleotide repeat disorders. Molecular genetic studies and subsequent molecular biological studies have provided fascinating new insights into the pathogenesis of both disorders and there is now real hope for disease modifying treatment in the not too distant future for patients with Parkinson's disease or Huntington's disease.


Assuntos
Doença de Huntington/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Alelos , Animais , Expressão Gênica/genética , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Camundongos , Microglia/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteômica/métodos , Sinucleínas , Repetições de Trinucleotídeos/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
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