Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease–causing genes is indicated in presenile dementia with an overlapping clinical diagnosis

Primitive neuroectodermal tumor: Report of two cases and review of the literature

AbstractJ Thorac Cardiovasc Surg 2002;124:833-

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward

The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions

Size and shape of the repetitive domain of high molecular weight wheat gluten proteins. 1. Small angle neutron scattering

The solution structure of the central repetitive domain of high molecular weight (HMW) wheat gluten proteins has been investigated for a range of concentrations and temperatures using mainly small-angle neutron scattering. A representative part of the repetitive domain (dBl) was studied as well as an "oligomer" basically consisting of four dBl units, which has a length similar to the complete central domain. The scattering data over the entire angular range of both proteins are in quantitative agreement with a structural model based on a worm-like chain, a model frequently used in polymer theory. This model describes the "supersecondary, structure" of dBl and dB4 as a semiflexible cylinder with a length of about 235 and 900 Angstrom, respectively, and a cross-sectional diameter of about 15 Angstrom. The flexibility of both proteins is characterized by a persistence length of about 13 Angstrom. Their structures are thus quantitatively identical, which implies that the central HMW domain can be elongated while retaining its structural characteristics. It seems conceivable that the flexible cylinder results from a helical structure, which resembles the beta-spiral observed in earlier studies on gluten proteins and elastin. However, compared to the previously, proposed structure of a (stiff) rod, our experiments clearly indicate flexibility of the cylinder. (C) 2003 Wiley Periodicals, Inc

Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease–causing genes is indicated in presenile dementia with an overlapping clinical diagnosis

Are white matter lesions directly associated with cognitive impairment in patients with lacunar infarcts?

Forty-four patients (mean age 66, SD 8 years) with either clinical evidence of a focal lacunar syndrome (n = 36) or with disorders of memory or gait (n = 8) in the presence of a lacunar infarct on CT were studied for cognitive functioning and for the presence of white matter lesions on MRI. MR images were assessed by a neurologist and a neuroradiologist blinded to the clinical data. Thirty-six patients had one or more lacunar infarcts on CT or MRI (in the thalamus in 5, in the caudate nucleus in 3 and in the internal capsule or corona radiata in the remaining patients). Twelve patients had multiple infarcts. Severe lesions of the white matted were found in 13 patients, mild to moderate lesions in 20 patients. Scores on Digit Span, Digit Symbol and delayed recall of the 15-Words test were significantly lower in the group with severe lesions, whilst there was a trend in the same direction for the Cognitive part of the Cambridge Examination of Mental Disorders in the Elderly, the Trailmaking B, Stroop colour interference test and the delayed visual reproduction of the Wechsler Memory Scale. These findings suggest that diffuse lesions of the white matter are an independent factor in the pathogenesis of intellectual dysfunction, also in patients with lacunar infarcts, but a truly independent analysis is difficult because the most severe involvement of the white matter tended to be associated with the largest number of lacunar infarcts