RESUMEN
Alzheimer's disease is believed to begin with synaptic dysfunction caused by soluble Aß oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aß oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble Aß species always coexist, and therefore it is difficult to determine which pathologies are caused by Aß oligomers and which are caused by amyloid fibrils. Thus, no validity of the oligomer hypothesis was available until the Osaka mutation was discovered. This mutation, which was found in a Japanese pedigree of familial Alzheimer's disease, is the deletion of codon 693 of APP gene, resulting in mutant Aß lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates Aß oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer's disease can be induced by Aß oligomers alone. In this review, we describe the story behind the discovery of the Osaka mutation, summarize the mutant's phenotypes, and propose a mechanism of its recessive inheritance.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Enfermedad de Alzheimer/congénito , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Herencia , Homocigoto , Humanos , Japón , Ratones , Linaje , Fenotipo , Placa Amiloide/patología , Eliminación de SecuenciaRESUMEN
Cerebral small vessel disease (SVD) contributes to cognitive impairment and dementia. SVD may affect veins, but veins are difficult to detect with 1.5 and 3T MRI. We compared deep medullary veins (DMVs) visualized on 7T-MRI between patients with early Alzheimer's disease (eAD; nâ=â17) or amnestic MCI (aMCI; nâ=â12) and controls (nâ=â40). The number and density of DMVs was similar in patients and controls, but tortuosity was higher in eAD (Cohen's dâ=â0.7, 95% CI: 0.1-1.2, pâ=â0.02) and aMCI (Cohen's dâ=â0.8, 95% CI: 0.2-1.5, pâ=â0.01), independent of brain atrophy. Venous changes provide a new perspective on vascular involvement in dementia.
Asunto(s)
Enfermedad de Alzheimer/congénito , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/etiología , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/diagnóstico por imagen , Imagen por Resonancia Magnética , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Encéfalo/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , MasculinoRESUMEN
We report on a previously not recognized mutation in exon 6 of presenilin-1 (PSEN1) (c.520_522delCTG) in a male patient with early onset familial Alzheimer disease. The mutation results in the deletion of a leucine at amino acid position 174 of the protein. The index patient presented with progressive memory loss at 50 years of age. Initially, depression was the only ancillary symptom. At age 53 clinical diagnosis of early Alzheimer disease was made based on neuropsychological, neuroimaging, and CSF findings. The patient's father and his paternal grandmother also suffered from memory loss and cognitive decline. The clinical findings in the patient are similar to signs and symptoms in previously reported patients with missense mutations at codon 174 of PSEN1.
Asunto(s)
Enfermedad de Alzheimer/congénito , Enfermedad de Alzheimer/genética , Eliminación de Gen , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Presenilina-1/genética , Humanos , MasculinoRESUMEN
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Mutations in genes such as those encoding amyloid precursor protein (APP), presenilin 1 and presenilin 2, are responsible for early-onset familial AD. CASE PRESENTATION: In this study, we report a 275341 G > C (Val717Leu) mutation in the APP gene in a Japanese family with early onset AD by genetic screening. This mutation has previously been detected in European families. In the Japanese family we screened, the age at onset of AD was 47.1 ± 3.1 years old (n = 9; range, 42-52). The symptoms in the affected members included psychiatric vulnerability and focal signs such as pyramidal signs, epileptic seizures, and myoclonic discharges. An MR imaging study showed relatively mild atrophic changes in the bilateral hippocampus and cerebral cortices in all affected members compared with their clinical presentations. CONCLUSION: We conclude that the clinical features of Alzheimer's disease can be different even when caused by the same mutation in the APP gene. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes.
Asunto(s)
Enfermedad de Alzheimer/congénito , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Linaje , Polimorfismo de Nucleótido Simple/genética , Adulto , Femenino , Pruebas Genéticas , Humanos , Japón , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
Although many Alzheimer's disease (AD) patients have a family history of the disease, it is rarely inherited in a predictable way. Functional magnetic resonance imaging (fMRI) studies of nondemented adults carrying familial AD mutations provide an opportunity to prospectively identify brain differences associated with early AD-related changes. We compared fMRI activity of 18 nondemented autosomal dominant AD mutation carriers with fMRI activity in eight of their noncarrier relatives as they performed a novelty encoding task in which they viewed novel and repeated images. Because age of disease onset is relatively consistent within families, we also correlated fMRI activity with subjects' distance from the median age of diagnosis for their family. Mutation carriers did not show significantly different voxelwise fMRI activity from noncarriers as a group. However, as they approached their family age of disease diagnosis, only mutation carriers showed increased fMRI activity in the fusiform and middle temporal gyri. This suggests that during novelty encoding, increased fMRI activity in the temporal lobe may relate to incipient AD processes.
Asunto(s)
Enfermedad de Alzheimer/congénito , Enfermedad de Alzheimer/fisiopatología , Apolipoproteínas E/genética , Predisposición Genética a la Enfermedad/genética , Heterocigoto , Imagen por Resonancia Magnética/métodos , Lóbulo Temporal/fisiopatología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
We report a patient with early-onset autosomal dominant dementia. The CSF showed increased levels of tau protein and decreased amyloid beta (ratio 42:40) typical for Alzheimer's disease. Cerebral MRI revealed vascular lesions and white-matter changes around the posterior horns of the ventricles with only moderate atrophy of the brain. Susceptibility-weighted imaging detected multiple small hemorrhagic changes. Gene analysis revealed amyloid precursor protein (APP) locus duplication as the cause of hereditary Alzheimer's dementia. The co-occurrence of CSF changes typical for Alzheimer's disease and MRI findings of cerebral amyloid angiopathy is remarkable, as it is also described for APP locus duplication. In conjunction with a family history suggestive of hereditary dementia, such a constellation should lead to enhanced gene analysis.
Asunto(s)
Enfermedad de Alzheimer/congénito , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Heterocigoto , Fragmentos de Péptidos/genética , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
BACKGROUND: At cross-section, cognitively normal individuals (NL) with a maternal history of late-onset Alzheimer disease (AD) have reduced glucose metabolism (CMRglc) on FDG-PET in the same brain regions as patients with clinical AD as compared to those with a paternal and a negative family history (FH) of AD. This longitudinal FDG-PET study examines whether CMRglc reductions in NL subjects with a maternal history of AD are progressive. METHODS: Seventy-five 50- to 82-year-old NL received 2-year follow-up clinical, neuropsychological, and FDG-PET examinations. These included 37 subjects with negative family history of AD (FH-), 9 with paternal (FHp), and 20 with maternal AD (FHm). Two subjects had parents with postmortem confirmed AD. Statistical parametric mapping was used to compare CMRglc across FH groups at baseline, follow-up, and longitudinally. RESULTS: At both time points, the FH groups were comparable for demographic and neuropsychological characteristics. At baseline and at follow-up, FHm subjects showed CMRglc reductions in the parieto-temporal, posterior cingulate, and medial temporal cortices as compared to FH- and FHp (p < 0.001). Longitudinally, FHm had significant CMRglc declines in these regions, which were significantly greater than those in FH- and FHp (p < 0.05). CONCLUSIONS: A maternal history of Alzheimer disease (AD) predisposes normal individuals to progressive CMRglc reductions in AD-vulnerable brain regions, which may be related to a higher risk for developing AD.