Key words: autophagy, Beclin 1, 3-methyladenine, amyloid β, c-secretase inhibitor, cerebral infarction, thalamus, secondary degeneration-S-phenylglycine t-butyl ester; LC3, microtubule-associated protein 1 light chain 3A; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; RHRSP, stroke-prone renovascular hypertensive rats; shRNA, short-hairpin RNA Cerebral infarction can cause secondary degeneration of thalamus and delay functional recovery. However, the mechanisms underlying secondary degeneration are unclear. The present study aimed to determine the occurrence and contribution of autophagy to thalamic degeneration after cerebral infarction. Focal cerebral infarction was induced by distal middle cerebral artery occlusion (MCAO). Autophagic activation, Beclin 1 expression and amyloid b (Ab) deposits were determined by immunofluorescence, immunoblot and electron microscopy. Secondary damage to thalamus was assessed with Nissl staining and immunofluorescence analysis. Apoptosis was determined using TUNEL staining. The contribution of autophagy to the secondary damage was evaluated by shRNA-mediated downregulation of Beclin 1 and the autophagic inhibitor, 3-methyladenine (3-MA). The potential role of Ab in autophagic activation was determined with N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The results showed that the conversion of LC3-II, the formation of autophagosomes, and the levels of activated cathepsin B and Beclin 1 were significantly increased in the ipsilateral thalamus at 7 and 14 d after MCAO (p , 0.05 or 0.01). Both Beclin 1 knockdown and 3-MA treatment significantly reduced LC3-II conversion and autophagosome formation, which were accompanied by obvious decreases in neuronal loss, gliosis and apoptosis in the ipsilateral thalamus (p , 0.05 or 0.01). Additionally, DAPT treatment markedly reduced Ab deposits, which coincided with decreases in LC3-II conversion and autophagosome formation (p , 0.01). These results suggest that inhibition of autophagy by Beclin 1 knockdown can attenuate the secondary thalamic damage after focal cerebral infarction. Furthermore, Ab deposits may be involved in the activation of autophagy.
T he evolution of motor function after stroke typically follows 2 strictly different patterns. Patients either recover ≈70% of maximal potential recovery (proportional recovery [PROP]) or show limited or no recovery (poor recovery [POOR]). 1-3 However, reliable predictors of motor improvement in the acute stage of stroke are scarce. Acute performance of the upper extremity on the Fugl-Meyer assessment (FMA-UE) seems to have predictive value. 1,4,5 Typically, for acute stroke patients with mild-to-moderate motor impairment of the upper extremity, motor function improves within 6 months by a relative proportion that is ≈70% of patients' maximal potential recovery. 6,7 However, initial Fugl-Meyer score alone may not reliably predict recovery of motor function in patients with acute-stage severe motor impairment of the limbs. 1,4 In addition, diffusion tensor imaging (DTI) studies have reported that the use of fractional anisotropy (FA) of corticospinal tract (CST) alone to predict future motor function of the upper extremity in patients with stroke in the acute period is also unreliable. 8-11 Researchers have proposed that more accurate prognoses may be made by combining behavioral tests with magnetic resonance imaging (MRI) determinations of the functional or structural integrity of the ipsilesional corticomotor tract. 12,13 However, it has been reported that on the base of initial impairment , adding functional MRI task-related brain activation patterns (during hand closure task) to their prediction model did Background and Purpose-Initial clinical assessment or conventional diffusion tensor imaging parameters alone do not reliably predict poststroke recovery of motor function. Recently, local diffusion homogeneity (LDH) has been proposed to represent the local coherence of water molecule diffusion and can serve as a complementary marker for investigating white matter alterations of the brain. We aimed to determine whether a combination of initial clinical assessment and LDH could predict motor recovery after acute subcortical infarction. Methods-Standard upper extremity Fugl-Meyer assessment and diffusion tensor imaging were performed 1, 4, and 12 weeks after onset in 50 patients with subcortical infarction. Proportional recovery model residuals were used to assign patients to proportional recovery and poor recovery groups. Tract-based spatial statistics analysis was used to compare diffusion differences between proportional and poor recovery outcomes. Multivariate logistic regression model was used to identify the predictors of motor improvement within 12 weeks after stroke. Results-The poor recovery group had lower LDH than the proportional recovery group, mainly in the ipsilesional corticospinal tract in the superior corona radiate and posterior limb of internal capsule 1 week after stroke (P<0.005; family-wise error corrected). Multivariate logistic regression analysis indicated that both initial Fugl-Meyer assessment and LDH in the ipsilesional corticospinal tract in the superior corona radiate and posterio...
Abnormal β-amyloid (Aβ) deposits in the thalamus have been reported after cerebral cortical infarction. In this study, we investigated the association of Aβ deposits, with the secondary thalamic damage after focal cortical infarction in rats. Thirty-six stroke-prone renovascular hypertensive rats were subjected to distal middle cerebral artery occlusion (MCAO) and then randomly divided into MCAO, vehicle, and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) groups and 12 sham-operated rats as control. The DAPT was administered orally at 72 hours after MCAO. Seven days after MCAO, sensory function, neuron loss, and glial activation and proliferation were evaluated using adhesive removal test, Nissl staining, and immunostaining, respectively. Thalamic Aβ accumulation was evaluated using immunostaining and enzyme-linked immunosorbent assay (ELISA). Compared with vehicle group, the ipsilateral thalamic Aβ, neuronal loss, glial activation and proliferation, and the mean time to remove the stimulus from right forepaw significantly decreased in DAPT group. The mean time to remove the stimulus from the right forepaw and thalamic Aβ burden were both negatively correlated with the number of thalamic neurons. These findings suggest that Aβ deposits are associated with the secondary thalamic damage. Reduction of thalamic Aβ by γ-secretase inhibitor may attenuate the secondary damage and improve sensory function after cerebral cortical infarction.
J. Neurochem. (2012) 120, 564–573. Abstract Focal cerebral cortical infarction after distal middle cerebral artery occlusion causes β‐amyloid deposition and secondary neuronal degeneration in the ipsilateral ventroposterior nucleus of the thalamus. Several studies suggest that autophagy is an active pathway for β‐amyloid peptide generation. This study aimed to investigate the role of autophagy in thalamic β‐amyloid deposition and neuronal degeneration after cerebral cortical infarction in hypertensive rats. At 7 and 14 days after middle cerebral artery occlusion, neuronal death and β‐amyloid deposits were evident in the ipsilateral ventroposterior nucleus, and the activity of β‐site amyloid precursor protein (APP)‐cleaving enzyme 1, required for β‐amyloid peptide generation, was elevated in the thalamus. In correlation, both the number of cells showing punctate microtubule‐associated protein 1A light chain 3 fluorescence and levels of light chain 3‐II protein, an autophagosome marker, were markedly increased. Notably, most of the cells that over‐expressed β‐site APP‐cleaving enzyme 1 displayed punctate light chain 3 staining. Furthermore, the inhibition of autophagy with 3‐methyladenine significantly reduced the thalamic neuronal damage, β‐amyloid deposits, and β‐site APP‐cleaving enzyme 1 activity. These results suggest that autophagosomes accumulate within thalamic cells after cerebral cortical infarction, which is associated with thalamic β‐amyloid deposition and secondary neuronal degeneration via elevation of β‐site APP‐cleaving enzyme 1 level.
BackgroundTraditional magnetic resonance (MR) imaging can identify abnormal changes in ipsilateral thalamus in patients with unilateral middle cerebral artery (MCA) infarcts. However, it is difficult to demonstrate these early changes quantitatively. Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (MRS) are potentially sensitive and quantitative methods of detection in examining changes of tissue microstructure and metabolism. In this study, We used both DTI and MRS to examine possible secondary damage of thalamus in patients with corona radiata infarction.MethodsTwelve patients with unilateral corona radiata infarction underwent MR imaging including DTI and MRS at one week (W1), four weeks (W4), and twelve weeks (W12) after onset of stroke. Twelve age-matched controls were imaged. Mean diffusivity (MD), fractional anisotropy (FA), N-acetylaspartate (NAA), choline(Cho), and creatine(Cr) were measured in thalami.ResultsT1-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted, and T2-FLAIR imaging showed an infarct at unilateral corona radiate but no other lesion in each patient brain. In patients, MD was significantly increased at W12, compared to W1 and W4 (all P< 0.05). NAA was significantly decreased at W4 compared to W1, and at W12 compared to W4 (all P< 0.05) in the ipsilateral thalamus. There was no significant change in FA, Cho, or Cr in the ipsilateral thalamus from W1 to W12. Spearman's rank correlation analysis revealed a significant negative correlation between MD and the peak area of NAA, Cho, and Cr at W1, W4, and W12 and a significant positive correlation of FA with NAA at W1.ConclusionsThese findings indicate that DTI and MRS can detect the early changes indicating secondary damage in the ipsilateral thalamus after unilateral corona radiata infarction. MRS may reveal the progressive course of damage in the ipsilateral thalamus over time.
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