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1.
Alzheimers Dement ; 14(1): 43-53, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28738187

RESUMO

INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Adulto , Apolipoproteínas E/genética , Atrofia/etiologia , Atrofia/patologia , Encéfalo/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estatísticas não Paramétricas , Fatores de Tempo
2.
Dement Geriatr Cogn Disord ; 27(2): 182-6, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19202337

RESUMO

BACKGROUND/AIMS: CHMP2B mutations are a rare cause of familial frontotemporal dementia (FTD). The clinical syndrome is dominated by personality change and behavioural symptoms, but language, memory, calculation and praxis impairments are also seen early in the course of the disease. There are no detailed studies of brain imaging in CHMP2B mutation-associated FTD. This study aimed to investigate whether there were early or presymptomatic changes in this group of patients. METHODS: Subjects comprised 16 members of a Danish family with CHMP2B mutation-associated FTD. Nine subjects were presymptomatic mutation carriers with a control group of 7 mutation-negative family members. Volumetric MRI brain scans were performed on all subjects at two time points, and rates of volume change were compared between the two groups. RESULTS: We demonstrate that generalized atrophy occurs presymptomatically in CHMP2B gene mutation carriers. CONCLUSIONS: This finding suggests that mutations in CHMP2B have widespread effects throughout the brain, leading to a neuro-anatomical signature distinct from other diseases in the frontotemporal lobar degeneration spectrum.


Assuntos
Encéfalo/patologia , Demência/genética , Demência/patologia , Proteínas do Tecido Nervoso/genética , Idoso , Atrofia , Progressão da Doença , Complexos Endossomais de Distribuição Requeridos para Transporte , Família , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Proteínas tau/fisiologia
3.
Alzheimer Dis Assoc Disord ; 23(4): 410-4, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19950418

RESUMO

We report an isolated, slowly progressive, pure amnestic phenotype in a 59-year-old member of a family affected by autosomal dominant familial Alzheimer disease. Early-onset Alzheimer disease in this family was associated with a V717G mutation in the amyloid precursor protein gene (APP). Subjective impairment of episodic memory began in our subject at the age of 44 years and subsequent, longitudinal neuropsychologic assessment confirmed progressive, severe, global impairment of memory functions over a period of 14 years with preservation of other cognitive domains. The mean annual hippocampal atrophy rate, determined by volumetric magnetic resonance imaging was intermediate between values previously associated with cognitively normal individuals and those with sporadic Alzheimer disease.


Assuntos
Amnésia/diagnóstico , Amnésia/genética , Precursor de Proteína beta-Amiloide/genética , Mutação , Adulto , Idoso , Envelhecimento/genética , Envelhecimento/psicologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Amnésia/patologia , Atrofia , Progressão da Doença , Feminino , Glicina/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valina/genética
4.
Neurology ; 89(21): 2167-2175, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29070659

RESUMO

OBJECTIVES: To investigate whether serum neurofilament light (NfL) concentration is increased in familial Alzheimer disease (FAD), both pre and post symptom onset, and whether it is associated with markers of disease stage and severity. METHODS: We recruited 48 individuals from families with PSEN1 or APP mutations to a cross-sectional study: 18 had symptomatic Alzheimer disease (AD) and 30 were asymptomatic but at 50% risk of carrying a mutation. Serum NfL was measured using an ultrasensitive immunoassay on the single molecule array (Simoa) platform. Cognitive testing and MRI were performed; 33 participants had serial MRI, allowing calculation of atrophy rates. Genetic testing established mutation status. A generalized least squares regression model was used to compare serum NfL among symptomatic mutation carriers, presymptomatic carriers, and noncarriers, adjusting for age and sex. Spearman coefficients assessed associations between serum NfL and (1) estimated years to/from symptom onset (EYO), (2) cognitive measures, and (3) MRI measures of atrophy. RESULTS: Nineteen of the asymptomatic participants were mutation carriers (mean EYO -9.6); 11 were noncarriers. Compared with noncarriers, serum NfL concentration was higher in both symptomatic (p < 0.0001) and presymptomatic mutation carriers (p = 0.007). Across all mutation carriers, serum NfL correlated with EYO (ρ = 0.81, p < 0.0001) and multiple cognitive and imaging measures, including Mini-Mental State Examination (ρ = -0.62, p = 0.0001), Clinical Dementia Rating Scale sum of boxes (ρ = 0.79, p < 0.0001), baseline brain volume (ρ = -0.62, p = 0.0002), and whole-brain atrophy rate (ρ = 0.53, p = 0.01). CONCLUSIONS: Serum NfL concentration is increased in FAD prior to symptom onset and correlates with measures of disease stage and severity. Serum NfL may thus be a feasible biomarker of early AD-related neurodegeneration.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/fisiopatologia , Doenças Neurodegenerativas/sangue , Proteínas de Neurofilamentos/sangue , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Estudos Transversais , Progressão da Doença , Saúde da Família , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/etiologia , Testes Neuropsicológicos , Presenilina-1/genética
5.
Neuroimage ; 38(2): 261-70, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17851093

RESUMO

The basal ganglia and thalamus are involved in processing all physiological behaviors and affected by many diseases. Accurate localization is a crucial issue in neuroimaging, particularly when working with groups of normalized images in a standard stereotaxic space. Here, manual delineation of the central structures (thalamus; nucleus caudatus and accumbens; putamen, pallidum, substantia nigra) was performed on 30 high resolution MRIs of healthy young adults (15 female, median age 31 years) in native space. Protocol inter-rater reliabilities were quantified as structure overlap (similarity indices, SIs). Structural volumes were calculated in native space, and after spatial normalization to stereotaxic space (MNI/ICBM152) and in relation to hemispheric volumes. Spatial extents relative to the anterior commissure (AC) were extracted. The 30 resulting atlases were then used to create probabilistic maps in stereotaxic space. Inter-rater SIs were high at 0.85-0.92 except for the nucleus accumbens. In native space, caudate, nucleus accumbens and putamen were significantly larger on the left, and the globus pallidus larger in males. After normalizing for brain volume, the nucleus accumbens, putamen and thalamus were larger on the left, with the gender difference in the globus pallidus still detectable. Some of these volume differences translated into significantly different distances from the AC. The probabilistic maps showed that overall the central structures' boundaries are relatively unchanged after spatial normalization. We present a comprehensive assessment of thalamic and basal ganglia volumetric and geometric data in both native and stereotaxic spaces. Probabilistic maps in MNI/ICBM152 space will allow accurate localization in group analyses.


Assuntos
Gânglios da Base/anatomia & histologia , Encéfalo/anatomia & histologia , Tálamo/anatomia & histologia , Gânglios da Base/fisiologia , Núcleo Caudado/anatomia & histologia , Núcleo Caudado/fisiologia , Globo Pálido/anatomia & histologia , Globo Pálido/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Modelos Neurológicos , Probabilidade , Putamen/anatomia & histologia , Putamen/fisiologia , Reprodutibilidade dos Testes , Tálamo/fisiologia
6.
Ann Neurol ; 57(5): 634-41, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15852377

RESUMO

Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4 cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment.


Assuntos
Cromossomos Humanos Par 1/genética , Di-Hidroxifenilalanina/análogos & derivados , Ligação Genética/genética , Paralisia Supranuclear Progressiva/genética , Idoso , Química Encefálica/fisiologia , Núcleo Caudado/diagnóstico por imagem , DNA/genética , Feminino , Glucose/metabolismo , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Compostos Radiofarmacêuticos , Paralisia Supranuclear Progressiva/diagnóstico por imagem
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