682 research outputs found
Long-term cognitive and functional decline in late onset Alzheimer's disease: therapeutic implications
No full textBackground: National Institute of Clinical Excellence guidelines advocate the use of the Mini-Mental Test Examination and a functional assessment as a means of measuring treatment response. However, there is little knowledge of the change expected in those with Alzheimer's disease in clinical practice. Objective: to describe the long-term variability of the Mini-Mental Test Examination and Blessed Dementia Rating Scale. Method: 374 Alzheimer's disease patients referred to psychiatric services in southeast London were followed annually over a 3-year period. Results: the mean Mini-Mental Test Examination score for the total group at baseline was 9.9 points. Individual variability in the rate of cognitive and functional decline is large and around 40% of patients after 1 year, and up to one-quarter of patients after 3 years who survived, show no change or an improvement in scores compared with baseline measures. Conclusions: in the evaluation of individual treatment response the rate of change, as measured by the Mini-Mental Test Examination and Blessed Dementia Rating Scale, is of limited value. <br/
The clinical phenotype of familial and sporadic late onset Alzheimer's disease
No full textBackground: familial factors are clearly associated with an increased risk of developing late onset Alzheimer's disease (LOAD). However, there is emerging evidence to suggest that familial factors may also influence clinical phenotype. To date, most studies have focussed on familial influences upon age of onset or duration of illness and few studies have compared the frequency of non-cognitive symptoms between familial and sporadic LOAD.Objective: to describe the clinical phenotype, with an emphasis on non-cognitive symptoms, of patients with LOAD and to explore familial differences.Method: 374 patients with LOAD were recruited from the community based Camberwell Dementia Case Register and a comparison made of the clinical phenotype of patients with and without a first degree family history of dementia.Results: a first degree family history of dementia was found in 27% of fully ascertained cases. An earlier age of onset was found in familial cases (77.2 years compared to 78.3 years, p < 0.05). However, no other differences in clinical phenotype, including the rate of cognitive decline, duration or the frequency of non-cognitive symptoms, were found between familial and sporadic cases.Conclusions: apart from an earlier age of onset, patients with familial LOAD, as a group, do not have major differences in their clinical phenotype compared to patients with sporadic LOAD
TAp73 alpha induces tau phosphorylation in HEK293a cells via a transcription-dependent mechanism
No full textp73 and tau both play roles in neurodevelopment and neurodegeneration. In this pilot study we show by Western blotting that TAp73 alpha induces phosphorylation of human 2N4R tau at threonine-205 and at the PHF-1 epitope (serine366/serine404) in HEK293a cells. Neither the dominant negative isoform, Delta Np73, nor a transcriptionally inactive mutant TAp73 alpha(R292H) altered tau phosphorylation indicating that tau phosphorylation is dependent on the transcriptional activity of TAp73 alpha. Consistent with this, confocal microscopy revealed that tau and TAp73 alpha were spatially separated within the cell; tau being located in the cytoskeletal compartment whilst TAp73 alpha was found in the nucleus. These findings have ramifications for microtubule dynamics associated with axonal growth during development and for neuronal death associated with Alzheimer's disease and other tauopathies. (c) 2006 Elsevier Ireland Ltd. All rights reserved
Overexpression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions
No full textSynaptic dysfunction is believed to be an early pathological change in neurodegenerative diseases and may cause the earliest clinical symptoms. We have used Drosophila to model a tauopathy in order to analyse the earliest neuronal and synaptic dysfunction. Our work has shown that overexpression of human tau (0N3R) in larval motor neurons causes a disruption of axonal transport and a morphological and functional disruption of NMJs (neuromuscular junctions). Tau-expressing NMJs are smaller with an abnormal structure. Despite abnormal morphology, tau-expressing NMJs retain synaptotagmin expression and can form active zones. Tau-expressing NMJs are functionally abnormal and exhibit disrupted vesicle cycling and synaptic transmission. At low-frequency stimulation (1 Hz), ESPs (evoked synaptic potentials) produced by tau-expressing motor neurons were indistinguishable from wild-type; however, following high-frequency stimulation (50 Hz), ESPs from tau-expressing NMJs were significantly decreased in amplitude. To investigate the mechanism underlying the change in ESPs, we analysed the relative numbers and distribution of mitochondria. This revealed that motor neurons expressing tau had a significant reduction in the number of detectable mitochondria in the pre-synaptic terminal. Our results demonstrate that tau overexpression results in synaptic dysfunction, associated with a reduced complement of functional mitochondria. These findings suggest that disruption of axonal transport and synaptic transmission may be key components of the pathogenic mechanism that underlie neuronal dysfunction in the early stages of tauopathies
Psychosis and aggression in Alzheimer's disease: the effect of dopamine receptor gene variation
No full textThis study investigated possible associations between selected polymorphisms in the dopamine receptor genes DRD1 and DRD3 with the presence of psychotic phenomena or aggressive behaviour in a community based cohort of 134 patients with late onset Alzheimer's disease. An association was found between the presence of psychotic symptoms and aggressive behaviour and the DRD1 polymorphism and between the presence of psychosis, but not aggression, and the DRD3 polymorphism. Specifically, carriers of the DRD1 B2 allele were more likely to be aggressive or experience hallucinations whereas homozygous carriers of the DRD3 1 allele were more likely to experience delusions
Endocytosis, synaptic transmission and mitochondria are defective in the neuromuscular junction in drosophila larvae over-expressing tau
No full textTAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in primary neurons
No full textp73, like Notch, has been implicated in neurodevelopment and in the maintenance of the mature central nervous system. In this study, by the use of reporter-gene assays, we demonstrate that C-promoter binding factor-1 (CBF-1)-dependent gene transcription driven by the Notch-1 intracellular domain (N1(ICD)) is potently antagonized by exogenously expressed transactivating (TA) p73 splice variants in SH-SY5Y neuroblastomas and in primary neurones. Time course analysis indicated that the inhibitory effects of TAp73 are direct and are not mediated via the product of a downstream target gene. We found that endogenous TAp73 stabilized by either c-Abl or cisplatin treatment also potently antagonized N1(ICD)/CBF-1-dependent gene transcription. Furthermore, western blotting revealed that exogenous TAp73 suppressed endogenous hairy and enhancer of split-1 (HES-1) protein levels and antagonized the increase in HES-1 protein induced by exogenous N1(ICD) expression. Evidence of a direct physical interaction between N1(ICD) and TAp73 alpha was demonstrated by co-immunoprecipitation. Using Notch deletion constructs, we demonstrate that TAp73 alpha binds the N1(ICD) in a region C-terminal of aa 2094. Interestingly, Delta Np73 alpha and TAp73 alpha(R292H) also co-purified with N1(ICD), but neither inhibited N1(ICD)/CBF-1-dependent transcription. This suggests that an intact transactivation (TA) domain and the ability to bind DNA are necessary for TAp73 to antagonize Notch signalling. Finally we found that TAp73 alpha reversed the N1(ICD)-mediated repression of retinoic acid-induced differentiation of SH-SY5Y neuroblastomas, providing functional evidence for an inhibitory effect of TAp73 alpha on notch signalling. Collectively, these findings may have ramifications for neurodevelopment, neurodegeneration and oncogenesis
Imaging A beta and tau in early stage Alzheimer's disease with [F-18]AV45 and [F-18]AV1451
No full textBackground:
AD is a progressive neurodegenerative disorder that is associated with the accumulation of two different insoluble protein aggregates, Aβ plaques and hyperphosphorylated tau. This study aimed to investigate the optimal acquisition and quantification of [18F]AV45 and [18F]AV1451 to image Aβ and tau, respectively, in subjects with AD.
Fifteen subjects with early stage AD underwent a T1-weighted structural MRI and two dynamic PET scans to image Aβ (60 min, [18F]AV45) and tau (120 min, [18F]AV1451). Both dynamic BPND and static SUVR outcome measures were calculated and compared for 12 out of 15 subjects who completed 60 min of the Aβ PET scan and at least 110 min of the tau PET scan. The SRTM and reference Logan graphical analysis were applied to the dynamic data to estimate regional BPND values and SUVR ratios from the static data. Optimal acquisition windows were explored for both the dynamic and static acquisitions. In addition, the spatial correlation between regional Aβ and tau signals was explored.
Results:
Both the SRTM and graphical analysis methods showed a good fit to the dynamic data for both Aβ and tau dynamic PET scans. Mean regional BPND estimates became stable 30 min p.i. for [18F]AV45 and 80 min p.i. for [18F]AV1451.
Time stability analysis of static SUVR data showed that the outcome measure starts to become stable for scan windows of 30–50 min p.i. for [18F]AV45 and 80–100 min p.i. for [18F]AV1451. The results from these time windows correlated well with the results from the full dynamic analysis for both tracers (R2 = 0.74 for [18F]AV45 and R2 = 0.88 for [18F]AV1451). There was a high correlation between amyloid uptake estimate using both dynamic analysis methods in thalamus and tau uptake in thalamus, hippocampus and amygdala.
Conclusions:
Short static PET scans at appropriate time windows provided SUVR values which were in reasonable agreement with BPND values calculated from dynamic scans using SRTM and reference Logan. These simplified methods may be appropriate for classification and intervention studies, although caution should be employed when considering interventional studies where blood flow and extraction could change
Depression in Alzheimer's disease: the effect of serotonin receptor gene variation
No full textThis study investigated possible associations between selected polymorphisms in the serotonin receptor genes, 5-HT2A and 5-HT2C, with the presence of co-morbid depressive illness at baseline in a community based cohort of 158 patients with late onset patients with Alzheimer's disease (AD). An association was found between the presence of major depressive illness at baseline and both the 5-HT2A and 5-HT2C polymorphisms. Specifically, homozygous carriers of the 5-HT2A C102 allele were five times more likely to have major depressive illness than heterozygotes. In addition, homozygous or hemizygous carriers of the 5-HT2C Ser allele were 12 times more likely to have major depressive illness than homozygous or hemizygous carriers of the 5-HT2C Cys allele
p53 is upregulated in Alzheimer's disease and induces tau phosphorylation in HEK293a cells
No full textp53 and tau are both associated with neurodegenerative disorders. Here, we show by Western blotting that p53 is upregulated approximately 2-fold in the superior temporal gyrus of Alzheimer's patients compared to healthy elderly control subjects. Moreover, p53 was found to induce phosphorylation of human 2N4R tau at the tau-1/AT8 epitope in HEK293a cells. Confocal microscopy revealed that tau and p53 were spatially separated intracellularly. Tau was found in the cytoskeletal compartment, whilst p53 was located in the nucleus, indicating that the effects of p53 on tau phosphorylation are indirect. Collectively, these findings have ramifications for neuronal death associated with Alzheimer's disease and other tauopathies. (c) 2007 Elsevier Ireland Ltd. All rights reserved
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