Hypoperfusion In Alzheimer's Disease Research Articles

Contribution of Beta‐amyloid Accumulation to Cerebral Hypoperfusion in Alzheimer's Disease

Alzheimer’s Disease (AD) is an emerging global health care crisis. However, underlying mechanisms are not understood well enough to translate to precision medicine. There is increasing evidence suggesting that AD is associated with brain hypoperfusion. However, it is unclear whether amyloid‐beta (Aβ) accumulation is a cause or consequence of AD, and how it contributes to cerebral hypoperfusion. The present study examined if Aβ accumulation induces cerebral hypoperfusion in AD by affecting cerebral vascular function via both anterograde (arteriole‐to‐capillary) and retrograde (capillary‐to‐arteriole) pathways in the TgF344‐AD rat model of Alzheimer's disease. We first confirmed that AD rats displayed hippocampal‐based cognitive dysfunction at 6 months of age using an eight‐arm water maze. We then found that AD rats exhibited impaired myogenic response (MR) of middle cerebral arteries (MCAs) and penetrating and parenchymal arterioles (PAs) two months earlier than the onset of cognitive deficits using a Living System pressure myograph. AD rats displayed poor surface and deep cortical cerebral blood flow (CBF) autoregulation recorded by laser Doppler flowmetry, and reduced functional hyperemic response induced by whisker stimulation. Moreover, cell contractile capabilities, detected by collagen gel based‐cell contraction kit, were reduced in Aβ‐treated cerebral VSMCs isolated from F344 rats, similar as seen in VSMCs isolated from AD rats. Furthermore, we found that the productions of reactive oxygen species (ROS) and mitochondrial superoxide in cerebral VSMCs isolated from AD rats were elevated using DHE staining and MitoSOX staining. Moreover, AD cells exhibited reduced mitochondrial respiration and ATP production detected by the Seahorse Cell Mito Stress Test kit. AD cerebral VSMCs also exhibited disrupted actin cytoskeleton and contractile units utilizing immunohistochemistry. Oxidative stress, mitochondrial dysfunction, and actin cytoskeleton disorganization are all factors that are associated with the reduced contractile capabilities of cerebral VSMCs mediated MR and CBF autoregulation. In other studies, we found that capillary endothelial cell‐derived inward rectifier potassium (Kir2.1) activity, which is responsible for retrograde CBF regulation, was reduced in the brain of AD rats using Western blot. PAs with capillaries isolated from AD rats dilated to a lesser degree than WT rats in response to moderately elevated extracellular K+ (10 mM) applied to capillaries. Inhibition of Kir2.1 channels with ML133 diminished the vasodilatory response to a greater extent in WT rats. These findings indicate that Aβ accumulation is associated with cerebral hypoperfusion in AD by affecting cerebral vascular function via both anterograde and retrograde pathways and provide novel insight into the vascular contribution to AD.

Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia.

In vascular dementia (VaD) and Alzheimer’s disease (AD), cerebral hypoperfusion and blood‐brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin‐associated glycoprotein to proteolipid protein‐1 (MAG:PLP1), a post‐mortem biochemical indicator of the adequacy of ante‐mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood‐brain barrier (BBB) leakiness; the level of vascular endothelial growth factor‐A (VEGF), a marker of tissue hypoxia; and endothelin‐1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age‐matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aβ and phospho‐tau parenchymal load, and Braak tangle stage. Aβ40 and Aβ42 were measured by ELISA in guanidine‐HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aβ level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD—limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aβ‐, tau‐ and endothelin‐related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases.

Cerebral Microbleeds Are Associated with Cerebral Hypoperfusion in Patients with Alzheimer's Disease.

BACKGROUND Although cerebral microbleeds (CMBs) are commonly observed in patients with Alzheimer's disease (AD), their clinical relevance for AD remains unclear. OBJECTIVE We investigated the significance of CMBs in AD by examining the relationship between CMBs and cerebral blood flow (CBF) in patients with AD. METHODS Thirty-four patients (aged 77.9±7.6 years; 17 men) with probable AD and multiple (≥8) CMBs were selected from 394 consecutive patients. For each lobe of the brain, the correlation between the number of CMBs observed on susceptibility-weighted images and the decrease in CBF observed on single-photon emission computed tomography was assessed. RESULTS The number of microbleeds was significantly correlated with the severity of decrease in the occipital lobe (Spearman's r = 0.531, p < 0.001) and temporal lobe (r = 0.437, p < 0.001) but not in the frontal lobe (r = 0.201, p = 0.101) and parietal lobe (r = 0.178, p = 0.146). These results were unchanged in the partial correlational analysis after controlling the effect of other small vessel disease such as lacunars and white matter hyperintensities. CONCLUSION Multiple CMBs are associated with cerebral hypoperfusion in AD. The effects of CMBs on CBF differed according to brain location, possibly reflecting different distributions of the underlying cerebral amyloid angiopathy and AD-related histopathology, such as neurofibrillary tangles.

Cerebral Microbleeds Are Associated with Cerebral Hypoperfusion in Patients with Alzheimer's Disease.

Although cerebral microbleeds (CMBs) are commonly observed in patients with Alzheimer's disease (AD), their clinical relevance for AD remains unclear. We investigated the significance of CMBs in AD by examining the relationship between CMBs and cerebral blood flow (CBF) in patients with AD. Thirty-four patients (aged 77.9±7.6 years; 17 men) with probable AD and multiple (≥8) CMBs were selected from 394 consecutive patients. For each lobe of the brain, the correlation between the number of CMBs observed on susceptibility-weighted images and the decrease in CBF observed on single-photon emission computed tomography was assessed. The number of microbleeds was significantly correlated with the severity of decrease in the occipital lobe (Spearman's r = 0.531, p < 0.001) and temporal lobe (r = 0.437, p < 0.001) but not in the frontal lobe (r = 0.201, p = 0.101) and parietal lobe (r = 0.178, p = 0.146). These results were unchanged in the partial correlational analysis after controlling the effect of other small vessel disease such as lacunars and white matter hyperintensities. Multiple CMBs are associated with cerebral hypoperfusion in AD. The effects of CMBs on CBF differed according to brain location, possibly reflecting different distributions of the underlying cerebral amyloid angiopathy and AD-related histopathology, such as neurofibrillary tangles.

VEGFR1 and VEGFR2 in Alzheimer's Disease.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-β, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

Effects of hypoperfusion in Alzheimer's disease.

The role of hypoperfusion in Alzheimer's disease (AD) is a vital component to understanding the pathogenesis of this disease. Disrupted perfusion is not only evident throughout disease manifestation, it is also demonstrated during the pre-clinical phase of AD (i.e., mild cognitive impairment) as well as in cognitively healthy persons at high-risk for developing AD due to family history or genetic factors. Studies have used a variety of imaging modalities (e.g., SPECT, MRI, PET) to investigate AD, but with its recent technological advancements and non-invasive use of blood water as an endogenous tracer, arterial spin labeling (ASL) MRI has become an imaging technique of growing popularity. Through numerous ASL studies, it is now known that AD is associated with both global and regional cerebral hypoperfusion and that there is considerable overlap between the regions implicated in the disease state (consistently reported in precuneus/posterior cingulate and lateral parietal cortex) and those implicated in disease risk. Debate exists as to whether decreased blood flow in AD is a cause or consequence of the disease. Nonetheless, hypoperfusion in AD is associated with both structural and functional changes in the brain and offers a promising putative biomarker that could potentially identify AD in its pre-clinical state and be used to explore treatments to prevent, or at least slow, the progression of the disease. Finally, given that perfusion is a vascular phenomenon, we provide insights from a vascular lesion model (i.e., stroke) and illustrate the influence of disrupted perfusion on brain structure and function and, ultimately, cognition in AD.

Visual attention deficits in Alzheimer's disease: Relationship to HMPAO SPECT cortical hypoperfusion

Patients with Alzheimer's disease (AD) display a multiplicity of cognitive deficits in domains such as memory, language, and attention, all of which can be clearly linked to the underlying neuropathological alterations. The typical degenerative changes occur early on in the disease in the temporal–parietal lobes, with other brain regions, such as the frontal cortex, becoming more affected as the disease progresses. In light of the importance of the parietal cortex in mediating visuospatial attentional processing, in the present study, we investigated a deficit in covert orienting of visual attention and its relationship to cortical hypoperfusion in AD. We characterized the visual attentional profile of 21 AD patients, relative to that of 26 matched normal individuals, and then assessed the correspondence between behavior and hypoperfusion, as measured by regional cerebral blood flow using SPECT. Relative to controls, the AD group demonstrated a unilateral attentional deficit, with disproportionate slowing in reorienting attention to targets in the left compared to the right hemispace, especially following an invalid peripheral cue. Furthermore, even in the presence of bilateral pathology typical of AD, there was a positive correlation between this unilateral attentional disorder and the magnitude of the right superior parietal lobe hypoperfusion. The association of the altered attentional processing profile (i.e., greater difficulty disengaging attention from right-sided stimuli) with right-hemisphere-predominant hypoperfusion not only confirms the critical role of the right parietal lobe in covert attentional orienting but, more importantly, identifies a potential locus of the behavioral alterations in visuospatial processing in AD.

Quantitative measurement of cerebral hypoperfusion and atrophy in Alzheimer's disease using MRI

Regional anatomic abnormalities (atrophy) are well known from studies of structural MRI in Alzheimer's disease (AD) when compared to cognitively normal (CN) subjects. Regional perfusion abnormalities due to metabolic changes are also expected in AD and have been studied mainly using FDG-PET. In this study, we tested the utility of Arterial-Spin Labeling MRI (ASL-MRI) for measuring cerebral blood flow in AD. We also compared the topography of cerebral hypoperfusion and atrophy in AD. Measuring perfusion and structural changes simultaneously should improve the understanding of AD. We compared 67 CN and 29 AD subjects who were similar in age, gender and education and were scanned on a 3T MRI scanner. 3D ASL-MRI and 3D T1-weighted Structural MRI (sMRI) were obtained on all subjects. The cerebral blood flow maps (CBF) were computed using the ASL-MRI pulse sequence and were co-registered to the sMRI. The gray matter density (GM) from sMRI and CBF of each patient was parcellated by normalizing an in-house modified AAL atlas with 118 regions-of-interest (ROI) to the patient's sMRI. The GM was used for partial volume correction (PVC) of the CBF maps at the voxel level. The regions of hypoperfusion in AD when compared to CN were bilateral posterior cingulate, precuneus and right superior parietal lobe (p < 0.05). The regions of GM atrophy were bilateral temporal and parietal lobes (p < 0.05). We found that PVC was an important step in the computation of perfusion differences since it reduces the number of false positive hypoperfusion regions that are observed due to atrophy. In this study, we found evidence that 1) ASL-MRI can be very useful for measuring CBF in AD subjects and shows regions of hypoperfusion similar to FDG-PET studies in the literature; 2) atrophy and hypoperfusion patterns in AD overlap but also contain some complementary information regarding the disease.

Simultaneous Measurement of Arterial Transit Time, Arterial Blood Volume, and Cerebral Blood Flow Using Arterial Spin-Labeling in Patients with Alzheimer Disease

Cerebral hemodynamics abnormality in Alzheimer disease (AD) is not fully understood. Our aim was to determine whether regional hypoperfusion due to AD is associated with abnormalities in regional arterial blood volume (rABV) and regional arterial transit time (rATT) as measured by quantitative arterial spin-labeling (ASL) with multiple-delay time sampling. Nineteen patients with AD (9 men and 10 women; mean age, 74.5 +/- 8.6 years) and 22 cognitively healthy control subjects (11 men and 11 women; mean age, 72.8 +/- 6.8 years) were studied by using a quantitative ASL method with multiple-delay time sampling. From the ASL data, maps of regional cerebral blood flow (rCBF), rABV, and rATT were generated. A region of hypoperfusion due to AD was determined by statistical parametric mapping (SPM) analysis. Mean rCBF, rABV, and rATT values within the hypoperfused region were compared between the AD and control groups. Despite the significantly lower rCBF (P = .0004) in patients with AD (27.8 +/- 7.1 mL/100 g/min) in comparison with control subjects (36.7 +/- 6.3 mL/100 g/min), no significant difference in rATT was observed between the control (0.48 +/- 0.09 seconds) and AD (0.47 +/- 0.10 seconds) groups. Mean rABV was lower in the AD group (0.22 +/- 0.10%) than in the control group (0.27 +/- 0.12%), though the difference did not reach the level of statistical significance. Our results revealed that regional hypoperfusion in AD is not associated with rATT prolongation, suggesting that the mechanism of hypoperfusion is distinct from that in cerebrovascular diseases.

The relationship between depressive symptoms and prefrontal hypoperfusion demonstrated by eZIS in patients with DAT

Depressive symptoms are common in Alzheimer's disease (AD) and contribute to clinical morbidity. Previous studies have suggested that hypoperfusion in the prefrontal cortex and anterior cingulate gyrus are involved in the pathophysiology of depression. Using the easy Z-score imaging system (eZIS), we investigated the relationship between depressive symptoms and prefrontal hypoperfusion in AD. Tc-99m-ethyl cysteinate dimer (Tc-99m-ECD)-single photon emission tomography (SPECT) and Neuropsychiatric Inventory (NPI) were performed in forty-four patients diagnosed as having Dementia of Alzheimer's type (DAT) with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). These patients were divided into the depressive group (D group: n=26) and non-depressive group (ND group: n=18) using NPI depression items. All data from SPECT images were analyzed using eZIS software. Scores in four regions were determined by Z-values; these regions consisted of each side of the prefrontal cortex and anterior cingulate gyrus. The mean scores between the D group and ND group were compared. The mean scores of the left prefrontal cortex in the D group were significantly higher (p<0.0125) than those in the ND group. There were no significant differences in the scores of the right prefrontal cortex and the bilateral anterior cingulate gyrus between these two groups (Mann-Whitney U-test). These findings suggest that hypoperfusion in the left prefrontal area contributes to the expression of depressive symptoms in patients with DAT.

Effect of linearization correction on statistical parametric mapping (SPM): A99mTc-HMPAO brain perfusion SPECT study in mild Alzheimer’s disease

Statistical parametric mapping (SPM) was employed to investigate the regional decline in cerebral blood flow (rCBF) as measured by 99mTc-hexamethyl propylene amine oxime (HMPAO) single photon emission computed tomography (SPECT) in mild Alzheimer's disease (AD). However, the role of the post reconstruction image processing on the interpretation of SPM, which detects rCBF pattern, has not been precisely studied. We performed 99mTc-HMPAO SPECT in mild AD patients and analyzed the effect of linearization correction for washout of the tracer on the detectability of abnormal perfusion. Eleven mild AD (NINCDS-ADRDA, male/female, 5/6; mean+/-SD age, 70.6+/-6.2 years; mean+/-SD mini-mental state examination score, 23.9+/-3.41; clinical dementia rating score, 1) and eleven normal control subjects (male/female, 4/7; mean+/-SD age, 66.8+/-8.4 years) were enrolled in this study. 99mTc-HMPAO SPECT was performed with a four-head rotating gamma camera. We employed linearization uncorrected (LU) and linearization corrected (LC) images for the patients and controls. The pattern of hypoperfusion in mild AD on LU and LC images was detected by SPM99 applying the same image standardization and analytical parameters. A statistical inter image-group analysis (LU vs. LC) was also performed. Clear differences were observed between the interpretation of SPM with LU and LC images. Significant hypoperfusion in mild AD was found on the LU images in the left posterior cingulate gyrus, right precuneus, left hippocampus, left uncus, and left superior temporal gyrus (cluster level, corrected p < 0.005). With the LC images, significant hypoperfusion in AD was found only in the bilateral posterior cingulate gyrus and left precuneus (cluster level, corrected p < 0.005). A pattern of greater rCBF distribution at the high flow cortices and low flow cortices was observed on LC and LU images, respectively, in the case of both controls and mild AD patients. Hippocampal hypoperfusion could be detected by means of SPM in the LU images but not in the LC images. The results of SPM may vary in 99mTc-HMPAO SPECT with or without linearization correction, which should be carefully evaluated when interpreting the pattern of rCBF changes in mild Alzheimer's disease.

Pattern of Cerebral Hypoperfusion in Alzheimer Disease and Mild Cognitive Impairment Measured with Arterial Spin-labeling MR Imaging: Initial Experience

To prospectively determine if pulsed arterial spin-labeling perfusion magnetic resonance (MR) imaging depicts regional cerebral hypoperfusion in subjects with Alzheimer disease (AD) and mild cognitive impairment (MCI), compared with perfusion in cognitively normal (CN) subjects, that is consistent with results of fluorodeoxyglucose (FDG) positron emission tomography (PET) and hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) studies of similar populations. Institutional review board approval and informed consent were obtained. Twenty subjects with AD (13 men, seven women; mean age, 72.9 years), 18 with MCI (nine men, nine women; mean age, 73.3 years), and 23 CN subjects (10 men, 13 women; mean age, 72.9 years) underwent arterial spin-labeling and volumetric T1-weighted structural MR imaging. Perfusion images were coregistered to structural images, corrected for partial volume effects (PVEs) with information from the structural image to determine tissue content of perfusion voxels, and normalized to a study-specific template. Analyses of perfusion differences between groups, with and without corrections for PVEs, were performed on a voxel-by-voxel basis with a one-tailed fixed-effects analysis of covariance model adjusted for age. In addition, tests were performed with and without accounting for global perfusion. The AD group showed significant regional hypoperfusion, compared with the CN group, in the right inferior parietal cortex extending into the bilateral posterior cingulate gyri (P <.001), bilateral superior and middle frontal gyri (P <.001), and left inferior parietal lobe (P=.007). When PVEs from underlying cortical gray matter atrophy were accounted for, the AD group still showed hypoperfusion in the right inferior parietal lobe extending into the bilateral posterior cingulate gyri (P <.001) and left (P=.003) and right (P=.012) middle frontal gyri. With a more liberal voxel-level threshold of P <.01, the MCI group showed significant regional hypoperfusion relative to the CN group in the inferior right parietal lobe (P=.046), similar to the region of greatest significance in the AD group. Arterial spin-labeling MR imaging showed regional hypoperfusion with AD, in brain regions similar to those seen in FDG PET and HMPAO SPECT studies of similar populations; this hypoperfusion persists after accounting for underlying cortical gray matter atrophy.

Bioethics and health education

Patients with Alzheimer's disease (AD) display a multiplicity of cognitive deficits in domains such as memory, language, and attention, all of which can be clearly linked to the underlying neuropathological alterations. The typical degenerative changes occur early on in the disease in the temporal–parietal lobes, with other brain regions, such as the frontal cortex, becoming more affected as the disease progresses. In light of the importance of the parietal cortex in mediating visuospatial attentional processing, in the present study, we investigated a deficit in covert orienting of visual attention and its relationship to cortical hypoperfusion in AD. We characterized the visual attentional profile of 21 AD patients, relative to that of 26 matched normal individuals, and then assessed the correspondence between behavior and hypoperfusion, as measured by regional cerebral blood flow using SPECT. Relative to controls, the AD group demonstrated a unilateral attentional deficit, with disproportionate slowing in reorienting attention to targets in the left compared to the right hemispace, especially following an invalid peripheral cue. Furthermore, even in the presence of bilateral pathology typical of AD, there was a positive correlation between this unilateral attentional disorder and the magnitude of the right superior parietal lobe hypoperfusion. The association of the altered attentional processing profile (i.e., greater difficulty disengaging attention from right-sided stimuli) with right-hemisphere-predominant hypoperfusion not only confirms the critical role of the right parietal lobe in covert attentional orienting but, more importantly, identifies a potential locus of the behavioral alterations in visuospatial processing in AD.

Determination of cerebral blood flow by SPECT:: A valuable tool in the investigation of dementia?

Positron emission tomography (PET) studies have demonstrated distinctive abnormalities in Alzheimer's disease (AD), multi-infarct-dementia (MID) and Pick's disease. Since PET is a complicated and expensive technique, its clinical application will be limited in the near future. An important finding in these PET studies is persistent coupling of brain metabolism and regional cerebral blood flow (rCBF). Therefore it should be possible to demonstrate bilateral temporoparietal hypometabolism as seen in patients with clinically diagnosed AD indirectly by measuring cerebral blood flow by Single Photon Emission Computer Tomography (SPECT). We report our first experiences with SPECT in the differential diagnosis of dementia with four case histories. We demonstrated temporoparietal hypoperfusion in AD and frontal hypoperfusion in Pick's disease as shown previously by PET. We could not demonstrate a typical SPECT in MID. The main purpose of SPECT in MID could be exclusion of coexisting AD. Based on current knowledge the possibilities and the limitation of this new technique are discussed. It is concluded that rCBF-SPECT may be of value in the diagnosis of AD and Pick's disease. Before this method can be used in daily clinical routine, its diagnostic value should be established according to principles of clinical decision making.