Detection of changed regional cerebral blood flow in mild cognitive impairment and early Alzheimer's dementia by perfusion-weighted magnetic resonance imaging
Department of Psychiatry and Psychotherapy, Heinrich Heine University, Bergische Landstrasse 2, D-40629, Duesseldorf, Germany.NeuroImage (Impact Factor: 6.36). 05/2008; 40(2):495-503. DOI: 10.1016/j.neuroimage.2007.11.053
The utility of perfusion-weighted magnetic resonance imaging (PW-MRI) for detecting changes in regional cerebral blood flow (rCBF) in patients with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) was evaluated. Thirteen cognitively normal (CN) elderly subjects, 35 mostly amnestic MCI subjects and 20 subjects with mild probable AD were enrolled. During i.v. injection of gadopentetate dimeglumine, a dynamic T2*-weighted single-shot EPI sequence was conducted using a 1.5-T scanner. Frontobasal (FROB), temporoparietal (TPAR), mesiotemporal (MTMP), anterior and posterior cingular (ACING, PCING), amygdala (AMYG), thalamus and cerebellar brain regions were studied. rCBF was computed from regional cerebral blood volume and arterial input function and normalised to white matter. Images were analysed by manually placed regions of interest using anatomical coregistration. Significant decreases of rCBF were detected in MCI vs. CN in MTMP (-23%), AMYG (-20%) and ACING (-15%) with no further decline in mild AD. In PCING hypoperfusion (-10%) was confined to AD. These hypoperfusional changes are a possible correlate of localised impairment of CNS function. In FROB no perfusion changes were observed between diagnostic groups, but hyperperfusion was observed in mild dementia stages, possibly reflecting functional compensatory mechanisms. These data suggest that PW-MRI detects specific changes in rCBF not only in AD, but also in amnestic MCI, a disorder suggested to largely represent a pre-dementia stage of AD. This method may thus be useful in both research and clinical applications to detect early functional brain changes in the pathogenesis of dementias.
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- "Increased atherosclerosis and microbleedings disrupt the regional blood flow in the cerebrovascular system and lead to hypoperfusion of the affected brain regions (Austin et al., 2011). Many studies have revealed that regional cerebral blood flow is decreased in MCI and in the early phase of AD, with the degree of disturbance correlating with the symptoms of dementia (Luckhaus et al., 2008; Wierenga et al., 2014). At the cellular level, a decrease in blood flow triggers hypoxia which stimulates an adaptive hypoxic response. "
ABSTRACT: We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the γ-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into γ-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis.
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- "CBF is decreased, and functional hyperemia is reduced in AD patients (Bateman et al. 2006; Hirao et al. 2005; Jagust et al. 1998; Johnson and Albert 2000; Luckhaus et al. 2008; Ruitenberg et al. 2005; Schroeter et al. 2007; Yoshiura et al. 2009). In particular, endothelium-dependent vasodilatation is altered in peripheral vessels of AD patients (Dede et al. 2007). "
ABSTRACT: Alzheimer's disease (AD) and cerebrovascular diseases share common vascular risk factors that have disastrous effects on cerebrovascular regulation. Endothelial cells, lining inner walls of cerebral blood vessels, form a dynamic interface between the blood and the brain and are critical for the maintenance of neurovascular homeostasis. Accordingly, injury in endothelial cells is regarded as one of the earliest symptoms of impaired vasoregulatory mechanisms. Extracellular buildup of amyloid-β (Aβ) is a central pathogenic factor in AD. Aβ exerts potent detrimental effects on cerebral blood vessels and impairs endothelial structure and function. Recent evidence implicates vascular oxidative stress and activation of the non-selective cationic channel transient receptor potential melastatin (TRPM)-2 on endothelial cells in the mechanisms of Aβ-induced neurovascular dysfunction. Thus, Aβ triggers opening of TRPM2 channels in endothelial cells leading to intracellular Ca(2+) overload and vasomotor dysfunction. The cerebrovascular dysfunction may contribute to AD pathogenesis by reducing the cerebral blood supply, leading to increased susceptibility to vascular insufficiency, and by promoting Aβ accumulation. The recent realization that vascular factors contribute to AD pathobiology suggests new targets for the prevention and treatment of this devastating disease.
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- "This is partially consistent with our findings in which reactive hypervolemia appears at the first week as a post-ischemic reperfusion response in the Aβ+CI model. Recent clinical studies using ASL or PW-MRI also revealed similar states of hyperperfusion in the hippocampus, cingulate gyrus, amygdala and striatum of patients with MCI and mild AD –. Our histopathology data showed that an increase in microvessel diameter, distributed sporadically throughout the striatal ischemic core at week 1, is consistent with vasodilation to maintain regional cerebral perfusion in response to the drop in CBF and CBV after ischemia was induced in CI and Aβ+CI rats. "
ABSTRACT: Background/Objective Clinical evidence indicates that cerebral ischemia (CI) and a pathological factor of Alzheimer's disease, the β-amyloid (Aβ) protein, can increase the rate of cognitive impairment in the ageing population. Using the CT Perfusion (CTP) functional imaging, we sought to investigate the interaction between CI and the Aβ protein on cerebral hemodynamics. Methods A previously established rat model of CI and Aβ was used for the CTP study. Iodinated contrast was given intravenously, while serial CT images of sixteen axial slices were acquired. Cerebral blood flow (CBF) and blood volume (CBV) parametric maps were co-registered to a rat brain atlas and regions of interest were drawn on the maps. Microvascular alteration was investigated with histopathology. Results CTP results revealed that ipsilateral striatum of Aβ+CI and CI groups showed significantly lower CBF and CBV than control at the acute phase. Striatal CBF and CBV increased significantly at week 1 in the CI and Aβ+CI groups, but not in the Aβ alone or control group. Histopathology showed that average density of dilated microvessels in the ipsilateral striatum in CI and Aβ+CI groups was significantly higher than control at week 1, indicating this could be associated with hyperperfusion and hypervolemia observed from CTP results. Conclusion These results demonstrate that CTP can quantitatively measure the hemodynamic disturbance on CBF and CBV functional maps in a rat model of CI interacting with Aβ.
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