حجم خون مغزی در بیماری آلزایمر و ارتباطش با تمامیت ساختاری بافت

A vascular component is increasingly recognized as important in Alzheimer's disease (AD). We measured cerebral blood volume (CBV) in patients with probable AD or Mild Cognitive Impairment (MCI) and in elderly non-demented subjects using a recently developed Vascular-Space-Occupancy (VASO) MRI technique. While both gray and white matters were examined, significant CBV deficit regions were primarily located in white matter, specifically in frontal and parietal lobes, in which CBV was reduced by 20% in the AD/MCI group. The regions with CBV deficit also showed reduced tissue structural integrity as indicated by increased apparent diffusion coefficients, whereas in regions without CBV deficits no such correlation was found. Subjects with lower CBV tended to have more white matter lesions in FLAIR MRI images and showed slower psychomotor speed. These data suggest that the vascular contribution in AD is primarily localized to frontal/parietal white matter and is associated with brain tissue integrity.

Alzheimer's disease (AD) is neurodegenerative disease associated with neuritic plaques composed of beta amyloid and neurofibrillary tangles composed of hyperphosphorylated tau protein. While amyloid/tau pathology is the primary focus in the field, recent evidence indicates that vascular factors are important in the pathogenesis of AD ( de la Torre, 2004). This evidence comes from a wide spectrum of studies, including postmortem studies showing severe cerebral angiopathy in AD patients ( Chui et al., 2006, Jagust et al., 2008 and Tian et al., 2006), epidemiologic studies showing that many of the risk factors for AD are also associated with vascular disease (hypertension, hypercholesterolemia, diabetes, and hyperhomocysteinemia) (reviewed in de la Torre (2002)), and neuroimaging studies showing that AD patients have greater volume of white matter hyperintensities of possible ischemic origin ( Delano-Wood et al., 2008 and Prins et al., 2004). Brain vascular function can be assessed by several different methods. For in vivo studies, cerebral blood flow (CBF), the amount of blood reaching the tissue per unit time (Kety and Schmidt, 1948), is the most widely used parameter. Previous CBF studies in AD patients have found pronounced blood flow deficits in temporoparietal cortex, posterior cingulate cortex, and in some cases, frontal cortex (Alsop et al., 2000, Bartenstein et al., 1997, Ishii et al., 1997, Johnson et al., 2005 and Kogure et al., 2000). CBF is known to be coupled to metabolic demand. Thus, although reduced CBF may be an indication of vascular dysfunction, it may also be simply due to lower metabolic demand in these regions (de Leon et al., 2001, Reiman et al., 2005 and Small et al., 2000) in the face of relatively intact brain vasculature. In addition, CBF is also governed by many factors external to the brain, such as cardiac output, autonomic activity, and blood pressure. Therefore, it is necessary to study brain vasculature in AD with alternative vascular parameters. Cerebral Blood Volume (CBV), the amount of blood per 100 ml of brain parenchyma, is an indicator of blood vessel lumen size and density. CBV has been less extensively studied than CBF, but was recently shown to be useful in assessing neovascularization in brain tumors (Law et al., 2004) and a good marker for angiogenesis and synaptogenesis (Pereira et al., 2007 and Swain et al., 2003). In addition, the sensitivity of CBV to physiologic variation is about 38% of that of CBF (Grubb et al., 1974). Thus, CBV may be less dependent on the subject's depth and rate of respiration. We have recently developed a Vascular-Space-Occupancy (VASO) Magnetic Resonance Imaging (MRI) technique to quantitate CBV (Lu et al., 2005). In contrast with the Dynamic Susceptibility Contrast (DSC) MRI method, the VASO approach is based on steady-state signal and does not depend on arterial input function, which itself may be changed with disease. CBV measured by VASO shows a moderate correlation with that using DSC MRI, but also displays some deviations (Lu et al., 2005), suggesting that the two measures may have slightly different physiologic bases. The VASO technique also has the advantage that the sensitivity is sufficient to assess vascular health in white matter, which is ordinarily very difficult to assess due to very low vascularity. In this study, we measured CBV in a group of patients with probable AD or Mild Cognitive Impairment (MCI), and identified regions with significant CBV decline compared to elderly non-demented controls. The relationship of CBV deficits to parenchymal damage was examined by correlating the regional CBV values to tissue water diffusion index as measured by diffusion tensor imaging (DTI), and the volume of white matter hyperintensities measured by FLAIR MRI. In addition, the CBV result was compared to neuropsychological test scores.

Vascular factors may contribute to the pathogenesis of AD. While both gray and white matter were examined, significant CBV deficit regions were primarily located in the white matter of the frontal and parietal lobes, in which CBV was reduced by ∼20% in the patient group. These CBV deficits correlated with parenchymal damage as assessed by diffusion tensor imaging and FLAIR MRI. In addition, the amount of CBV deficit also appeared to correlate with impairment of psychomotor speed.