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1.
Tau Ming Liew 《Journal of the American Medical Directors Association》2019,20(8):1054.e11-1054.e20
ObjectivesEarly diagnosis of cognitive impairment is increasingly emphasized in the literature to facilitate timely preventive interventions. Although bedside cognitive tests such as the Montreal Cognitive Assessment (MoCA) are widely used for such early diagnostic purposes, they may not have comparable performance to a full neuropsychological battery (FNB) in diagnosing early cognitive impairment. This study investigated whether a small subset of neuropsychological tests can be added on to MoCA to match its performance to that of the FNB in discriminating mild cognitive impairment and dementia (MCI/dementia) from normal cognition.DesignCross-sectional diagnostic study.SettingAlzheimer's Disease Centers across the United States.ParticipantsOlder participants (≥50 years) who completed MoCA and the FNB (N = 9187).MeasuresThe study sample was split into two: the derivation sample (n = 1837) was used to develop a brief neuropsychological battery that best discriminated MCI/dementia (using the best-subset approach with 10-fold cross-validation); while the validation sample (n = 7350) verified its actual performance in discriminating MCI/dementia.ResultsA 3-item neuropsychological battery was identified, comprising MoCA, Benson Complex Figure Recall, and Craft Story 21 Delayed Recall. It had excellent performance in discriminating MCI/dementia from normal cognition (area under the receiver operating characteristic curve [AUROC] 90.0%, 95% confidence interval [CI] 89.2%-90.7%), which was comparable to that of the FNB (AUROC 88.4%, 95% CI 87.6%-89.2%). By contrast, MoCA alone had significantly worse AUROC (86.9%, 95% CI 86.0%-87.7%) than that of the FNB.Conclusions/ImplicationsUsing rigorous methods, this study developed a brief neuropsychological battery that maintained the brevity of a bedside cognitive test, while rivaling the diagnostic performance of an FNB in early cognitive impairment. This brief battery offers a viable alternative when the FNB is needed but cannot be feasibly administered in nonspecialty clinics. It can have a wider health systems effect of improving patients’ access to accurate diagnosis in early cognitive impairment and facilitating timely interventions to delay the progression of cognitive impairment. 相似文献
2.
INTRODUCTIONThemicrotubule-associatedprotein蚲ishyperphos-phorylatedandglycosylatedinAlzheimerdisease(AD),andtheseabnormalmodificationsformedthebasisofprogressivelyretrogradeneurofibrillarydegenerationseeninADbrainandtherebythedementia(1,2).ADab-normallyphosphorylated蚲notonlyismicrotubuleas-semblyincompetent,butalsoinhibitsassemblyanddis-assemblesthepreassembledmicrotubulesinvitro(3).Inthetangle-bearingneuronsinADbrain,thenormalcytoskeletonisdisruptedandreplacedwi… 相似文献
3.
Neuropsychiatric disturbances are extremely common in Alzheimer’s disease (AD), and represent integral features of the illness,
as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence
of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved
to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent
on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle
formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally
in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these
studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or
some other mechanism, is a useful therapeutic agent to modify disease progression in AD. 相似文献
4.
K. Arima Minako Nakamura Nobuhiko Sunohara Masafumi Ogawa Midori Anno Yoko Izumiyama Shigeo Hirai Kazuhiko Ikeda 《Acta neuropathologica》1997,93(6):558-566
Coiled bodies and interfascicular threads are conspicuous white matter abnormalities of brains of patients with progressive
supranuclear palsy (PSP). Both structures are argyrophilic and immunoreactive for the microtubule-binding protein tau. This
report concerns the ultrastructural localization of interfascicular threads and their relationship to coiled bodies in five
PSP patients. We showed for the first time that abnormal tubules with a 13- to 15-nm diameter and fuzzy outer contours were
the common structures of coiled bodies in the oligodendroglial perikarya and of interfascicular threads. Moreover, the tubules
were immunolabeled by anti-tau antibodies. The abnormal tau-positive tubules of interfascicular threads were located in the
inner loop of the myelin sheath. Our study further indicated that the thread-like structures in the white matter comprised,
at least in part, oligodendroglial processes, and that they were also present in gray matter. We consider that the formation
of coiled bodies in the perikarya and of interfascicular threads represents a common cytoskeletal abnormality of the oligodendroglia
of PSP patients. Moreover, even though the white matter alterations of PSP resemble those of corticobasal degeneration, there
are certain ultrastructural differences in the abnormal oligodendroglial tubules of the two diseases.
Received: 4 October 1996 / Accepted: 6 December 1996 相似文献
5.
The neurotransmitter biosynthetic enzymes, tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) are each composed of
an amino-terminal regulatory domain and a carboxylterminal catalytic domain. A chimeric hydroxylase was generated by coupling
the regulatory domain of TH (TH-R) to the catalytic domain of TPH (TPH-C) and expressing the recombinant enzyme in bacteria.
The chimeric junction was created at proline 165 in TH and proline 106 in TPH because this residue is within a conserved five
amino-acid span (ValProTrpPhePro) that defines the beginning of the highly homologous catalytic domains of TH and TPH. Radioenzymatic
activity assays demonstrated that the TH-R/TPH-C chimera hydroxylates tryptophan, but not tyrosine. Therefore, the regulatory
domain does not confer substrate specificity. Although the TH-R/TPH-C enzyme did serve as a substrate for protein kinase (PKA),
activation was not observed following phosphorylation. Phosphorylation studies in combination with kinetic data provided evidence
that TH-R does not exert a dominant influence on TPH-C. Stability assays revealed that, whereas TH exhibited a t1/2 of 84 min at 37°C, TPH was much less stable (t
1/2=28.3 min). The stability profile of TH-R/TPH-C, however, was superimposable on that of TH. Removal of the regulatory domain
(a deletion of 165 amino acids from the N-terminus) of TH rendered the catalytic domain highly unstable, as demonstrated by
at
1/2 of 14 min. The authors conclude that the regulatory domain of TH functions as a stabilizer of enzyme activity. As a corollary,
the well-characterized instability of TPH may be attributed to the inability of its regulatory domain to stabilize the catalytic
domain. 相似文献
6.
Expression of tau protein in non-neuronal cells can result in a redistribution of the microtubule cytoskeleton into thick bundles of tau-containing microtubules (Lewis et al.: Nature 342:498-505, 1989; Kanai et al.: J Cell Biol 109:1173-1184, 1989). We reconstituted microtubule bundles using purified tubulin and tau in order to study the assembly of these structures. Taxol-stabilized tubulin polymers were incubated with various concentrations of recombinant human tau and examined by electron microscopy. With increasing concentrations of tau 3 (tau isoform containing three microtubule binding domains) or tau 4 (isoform containing four microtubule binding domains) the microtubules changed orientation from a random distribution to loosely and tightly packed parallel arrays and then to thick cables. In contrast, tau 4L, the tau isoform containing four microtubule binding domains plus a 58-amino acid insert near the N-terminus, showed minimal bundling activity. tau 4-induced bundling could be inhibited by the addition of 0.5 M NaCl or 0.4 mM estramustine phosphate, conditions which are known to inhibit tau binding to microtubules. A tau construct that contained only the microtubule binding domains plus 19 amino acids to the C-terminus was fully capable of bundling microtubules. Phosphorylation of tau 3 with cAMP-dependent protein kinase had no effect on its ability to induce microtubule bundling. These results indicate that tau protein is directly capable of bundling microtubules in vitro, and suggests that different tau isoforms differ in their ability to bundle microtubule filaments. 相似文献
7.
Eric Vivier Antonio J. da Silva Melissa Ackerly Herbert Levine Christopher E. Rudd Paul Anderson 《European journal of immunology》1993,23(8):1872-1876
The CD16: ζ: γ receptor complex allows natural killer (NK) cells to recognize and eliminate antibody-coated target cells. Whereas the ectodomain of CD16 is the receptor for Fcγ domains of immunoglobulins, disulfide-linked homo- and heterodimers composed of ζ and γ are required for the cell surface expression, and signal transduction properties of the complex. Engagement of CD16 activates the tyrosine kinase pathway, which induces the tyrosine phosphorylation of several substrates, including the ζ subunit and the phospholipase C γ-1 and γ-2 isoforms. Here we show that CD 16 stimulation of either peripheral blood NK cells, leukemic NK cells, or Jurkat transformants expressing a CD16:ζ:γ receptor complex, results in the tyrosine phosphorylation of a 70 kDa ζ-associated protein (pp70). Similarly, a 70-kDa ζ-associated phosphoprotein in T cells has been shown to be a tyrosine kinase (ZAP-70). Peptide mapping analysis indicates that the 70-kDa ζ-associated phosphoproteins from T cells and NK cells are structurally indistinguishable. We conclude that the CD16:ζ:γ complex may use a ZAP-70-related non-receptor tyrosine kinase, in the CD16 signaling cascade leading to NK cell activation. 相似文献
8.
Barbara Porton Adriana Ferreira Lynn E DeLisi Hung Teh Kao 《Neuropsychopharmacology》2004,55(2):118-125
BACKGROUND: Synapsin III plays a role in neuronal plasticity and maps to chromosome 22q12-13, a region suggested to be linked to schizophrenia. To determine if synapsin III plays a role in this disease, we searched for polymorphisms in this gene in patients with schizophrenia and controls. METHODS: The synapsin III gene was initially sequenced from 10 individuals with schizophrenia to identify polymorphisms. Association analysis was then performed using 118 individuals with schizophrenia and 330 population controls. Synapsin III expression was studied by immunoblot analyses, and phosphorylation sites were mapped by sequencing trypsin-digested synapsin III fragments phosphorylated with phosphorus-32. RESULTS: A rare, missense polymorphism, S470N, was identified in the synapsin III gene and appeared more frequently in individuals with schizophrenia than in controls (p =.0048). The site affected by the polymorphism, Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. Phosphorylation at Ser470 was increased during neonatal development and in response to neurotrophin-3 in cultured hippocampal neurons. CONCLUSIONS: Our observations suggest an association of a rare polymorphism in synapsin III with schizophrenia, but further studies will be required to clarify its role in this disease. 相似文献
9.
Yoichi Kushima Tomonori Fujiwara Masumi Sanada Kimio Akagawa 《Journal of molecular neuroscience : MN》1997,8(1):19-27
We raised polyclonal and monoclonal antibodies against rat recombinant HPC-1/syntaxin 1A lacking a transmembrane domain. The
polyclonal antibody recognized two major bands at 35 and 40 kDa from rat brain membranes. A hybridoma clone designated 14D8,
however, recognized only one band at 35 kDa. A polyclonal antibody detected recombinant syntaxin 1B, as well as HPC-1/syntaxin
1A on an immunoblot, whereas 14D8 recognized recombinant HPC-1/syntaxin 1A, but not syntaxin 1B. Therefore, 14D8 is specific
for HPC-1/syntaxin 1A. Using this monoclonal antibody, we investigated the expression of HPC-1/syntaxin 1A in the rat hippocampal
membranes.
HPC-1/syntaxin 1A was present even in the embryonic d 19 (E19) hippocampal membranes, and it increased during the next two
postnatal wk. Pyramidal cell axons were intensely stained with the 14D8 monoclonal antibody, suggesting that HPC-1/syntaxin
1A was not restricted to the presynaptic terminal. Furthermore, we investigated the phosphorylation of HPC-1/syntaxin 1A in
the rat brain membranes. HPC-1/syntaxin 1A affinity-purified on a 14D8 IgG-coupled column was recognized by antiphophoserine
antibody, but not by antiphosphotyrosine and phosphothreonine antibodies. 相似文献
10.