Is apolipoprotein E4 an important risk factor for vascular dementia?

Despite the fact that vascular dementia (VaD) represents the seconding leading cause of dementia in the USA, behind only Alzheimer’s disease (AD), there remains a lack of consensus on the pathological criteria required for diagnosis of this disease. A number of clinical diagnostic criteria exist but are poorly validated and inconsistently applied. It is clear that vascular risk factors play an important role in the etiology of VaD, including hypertension, stroke, diabetes, and atherosclerosis. Vascular risk factors may increase the risk for VaD by promoting inflammation, cerebral vascular disease, white matter lesions, and hippocampal sclerosis. Because vascular risk factors seem to impart a high degree of risk for conferring VaD, it seems logical that the apolipoprotein E (APOE) status of individuals may be important. APOE plays a critical role in transporting cholesterol in and out of the CNS and in AD it is known that harboring the APOE allele increases the risk of AD perhaps due to the improper functioning of this protein. The purpose of this review is to examine the important pathological features and risk factors for VaD and to provide a critical assessment of the current literature regarding whether or not apoE4 also confers disease risk in VaD. The preponderance of data suggests that harboring one or both APOE4 alleles elevates the risk for VaD, but not to the same extent as found in AD.     

Quantitative characterization of hemodynamic properties and vasculature dysfunction of high-grade gliomas

Aberrations in tumor and peritumoral vasculature may not be distinguishable by cerebral blood flow (CBF) or cerebral blood volume (CBV) alone. The relationships between CBF and CBV were examined to estimate vasculature-specific hemodynamic characteristics. Twenty glioma patients were studied with dynamic susceptibility T2*-weighted MRI [(dynamic contrast-enhanced magnetic resonance imaging (DSC-MRI)] before and during week 1 and 3 of radiotherapy (RT). CBF and CBV were calculated from DSC-MRI, and relationships between the two were evaluated: the physiological measure of mean transit time (MTT) = CBV/CBF; empirical fitting using the power law CBV = constant x (CBF)(beta). Three different tissue types were assessed: the Gd-enhancing tumor volume (GEV); non-enhanced abnormal tissue located beyond GEV but within the abnormal hyperintense region on FLAIR images (NEV); normal tissue in the hemisphere contralateral to the tumor (CNT). The effects of tissue types, CBV magnitudes (low, medium and high), before and during RT, on MTT and beta were analyzed by analysis of variance (ANOVA). The MTT and beta for the three tissue types were significantly different (p < 0.009). MTT increased from CNT (1.60 s) to NEV (1.93 s) to GEV (2.28 s) (p < 0.0005). beta was significantly greater in GEV (1.079) and NEV (1.070) than in CNT (1.025). Beta increased with increasing CBV magnitude while MTT was independent of CBV magnitude. There was a significant decrease in MTT of NEV and GEV during week 3 of RT compared with pre-RT values for all CBV magnitudes. There was a significant increase in beta during RT in the tumor and peritumor. Progressive abnormalities in vasculature and hemodynamic characteristics of the vascular bed were delineated, with significant disorder in the tumor but mild abnormality in peritumoral tissue.     

Separation of input function for rapid measurement of quantitative CMRO2 and CBF in a single PET scan with a dual tracer administration method

Cerebral metabolic rate of oxygen (CMRO(2)), oxygen extraction fraction (OEF) and cerebral blood flow (CBF) images can be quantified using positron emission tomography (PET) by administrating (15)O-labelled water (H(15)(2)O) and oxygen ((15)O(2)). Conventionally, those images are measured with separate scans for three tracers C(15)O for CBV, H(15)(2)O for CBF and (15)O(2) for CMRO(2), and there are additional waiting times between the scans in order to minimize the influence of the radioactivity from the previous tracers, which results in a relatively long study period. We have proposed a dual tracer autoradiographic (DARG) approach (Kudomi et al 2005), which enabled us to measure CBF, OEF and CMRO(2) rapidly by sequentially administrating H(15)(2)O and (15)O(2) within a short time. Because quantitative CBF and CMRO(2) values are sensitive to arterial input function, it is necessary to obtain accurate input function and a drawback of this approach is to require separation of the measured arterial blood time-activity curve (TAC) into pure water and oxygen input functions under the existence of residual radioactivity from the first injected tracer. For this separation, frequent manual sampling was required. The present paper describes two calculation methods: namely a linear and a model-based method, to separate the measured arterial TAC into its water and oxygen components. In order to validate these methods, we first generated a blood TAC for the DARG approach by combining the water and oxygen input functions obtained in a series of PET studies on normal human subjects. The combined data were then separated into water and oxygen components by the present methods. CBF and CMRO(2) were calculated using those separated input functions and tissue TAC. The quantitative accuracy in the CBF and CMRO(2) values by the DARG approach did not exceed the acceptable range, i.e., errors in those values were within 5%, when the area under the curve in the input function of the second tracer was larger than half of the first one. Bias and deviation in those values were also compatible to that of the conventional method, when noise was imposed on the arterial TAC. We concluded that the present calculation based methods could be of use for quantitatively calculating CBF and CMRO(2) with the DARG approach.     

Assessment of activation of the plasma kallikrein-kinin system in frontal and temporal cortex in Alzheimer's disease and vascular dementia

Decreased cerebral blood flow and blood-brain barrier disruption are features of Alzheimer's disease (AD). The plasma kallikrein-kinin system modulates cerebrovascular tone through release of vasoactive bradykinin (BK). Cerebroventricular infusion of Aβ1-40 enhances BK release, suggesting that the activity of this system may be elevated in AD. We investigated the profile of the activating protease of this system, plasma kallikrein (PK), in frontal and temporal brain tissue from postmortem confirmed cases of AD, vascular dementia (VaD), and controls. Measurements of neuron specific enolase messenger ribonucleic acid (mRNA) and protein were used to adjust for neuronal loss. Adjusted PK mRNA was significantly increased in the frontal cortex in AD, and the frontal and temporal cortex in VaD. Similar trends were seen for PK protein level in AD and VaD. PK activity was significantly increased in the frontal and temporal cortex in AD. Increased PK activity in AD is likely to contribute to increased BK release and may thereby influence cerebral blood flow and vascular permeability.     

Blood pressure and the risk for dementia—A double edged sword

Alzheimer's disease (AD) and vascular dementia (VaD) are important causes of cognitive decline in the elderly. As a result of the aging population, the incidence of dementia is expected to increase substantially over the coming decades. Many studies have identified that vascular risk factors are implicated in the pathogenesis of both AD and VaD. Longitudinal studies have suggested that high blood pressure in midlife is associated with a higher incidence of both AD and VaD in later life. The association appears weaker for hypertension in later life. Some studies also suggest that hypotension; especially low diastolic blood pressure in late-life is also associated with an increased risk of AD. Long-standing hypertension may lead to severe atherosclerosis and impaired cerebrovascular autoregulation. A decline in blood pressure in later life may contribute to diminished cerebral perfusion. The subsequent ischaemic state may lead to increased cerebral β-amyloid accumulation.     

Contribution of vascular pathology to the clinical expression of dementia

Vascular lesions in the brain are common with advancing age; however, the independent and cumulative contributions of postmortem vascular lesions to antemortem cognitive status are not well established. We examined association of six vascular lesions (large infarcts, lacunar infarcts, leukoencephalopathy, microinfarcts, cribriform changes, and cerebral amyloid angiopathy) with antemortem diagnoses of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in 190 older adults from an autopsy series. We also developed a summary score based on three macroscopic vascular lesions: large infarcts (0, 1, and >or=2), lacunar infarcts (0, 1, and >or=2), and leukoencephalopathy (none, mild, and moderate-to-severe). Sixty-eight percent of cases had vascular lesions. Only leukoencephalopathy was associated with dementia (odds ratio (OR) 3.5, 95% CI 1.0-12.4), and only large infarcts were associated with VaD (OR 4.3, 95% CI 1.2-15.4). The vascular score was associated with dementia (OR 1.6, 95% CI 1.2-2.3), AD (OR 1.5, 95% CI 1.0-2.1) and VaD (OR 2.0, 95% CI 1.4-3.0). Leukoencephalopathy, large infarcts, and higher vascular burden is associated with the clinical expression of dementia and subtypes.     

Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia

Alzheimer's disease (AD) and vascular dementia (VaD) are widely accepted as the most common forms of dementia. Cerebrovascular lesions frequently coexist with AD, creating an overlap in the clinical and pathological features of VaD and AD. This review assembles evidence for a role for cholinergic mechanisms in the pathogenesis of VaD, as has been established for AD. We first consider the anatomy and vascularization of the basal forebrain cholinergic neuronal system, emphasizing its susceptibility to the effects of arterial hypertension, sustained hypoperfusion, and ischemic cerebrovascular disease. The impact of aging and consequences of disruption of the cholinergic system in cognition and in control of cerebral blood flow are further discussed. We also summarize preclinical and clinical evidence supporting cholinergic deficits and the use of cholinesterase inhibitors in patients with VaD. We postulate that vascular pathology likely plays a common role in initiating cholinergic neuronal abnormalities in VaD and AD.     

CT灌注成像评价颅骨缺损修复前后 脑血流量变化的临床研究

目的 通过CT灌注成像（CTP）观察颅骨成形术患者脑血流量的变化。方法 对20例颅骨缺损修复的患者进行脑CT灌注成像,在颅骨修复术前和术后2周进行CTP。记录大脑皮层、基底节区脑血流容量（CBV）、脑血流流量（CBF）、造影剂平均通过时间（MMT）和对比剂达到峰值的时间（TTP）等所有参数,分析脑皮层和基底节区血流灌注数据的变化。结果 颅骨修复术前患侧脑皮层区的CBV和CBF值均低于健侧,TTP和MTT值均高于健侧,差异均具有统计学意义（P＜0.05）。修复术后患侧脑皮层的CBF、CBV值均有提高,患侧脑皮层的MTT、TTP值较术前降低,差异均具有统计学意义（P＜0.05）。患侧术后脑皮层的CBV、CBF、MTT、TTP值与健侧比较无统计学意义（P＞0.05）。结论 CT灌注成像能及时发现脑血流变化情况,颅骨修复可以增加脑皮层区脑血流量,促进神经功能恢复。     

Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease

Increasing evidence supports a role of oxidative imbalance, characterized by impaired antioxidant enzymatic activity and increased reactive oxygen species (ROS) production, in mild cognitive impairment (MCI) and Alzheimer's disease (AD) pathogenesis. Hyperhomocysteinemia, another risk factor for AD, also contributes to oxidative damage. Plasma total homocysteine (tHcy) and ROS levels, and total antioxidant capacity (TAC) were determined in 71 AD, 36 MCI and 28 vascular dementia (VaD) patients as well as in 44 age-matched controls. tHcy levels were significantly increased in patients with AD and VaD an a trend towards an increase in multiple domain MCI was observed. TAC was significantly decreased in AD as well as MCI, but not in VaD patients. In AD patients, a negative correlation was found between TAC and disease duration. ROS levels did not differ among groups, but were correlated with age. In conclusion, a pattern characterized by increased tHcy levels and decreased TAC is present in AD as well as MCI patients. While increased tHcy levels were also found in VaD, TAC modifications occur specifically in AD. ROS levels appear to be correlated with age rather than with a specific dementing disorder, thus leading to the hypothesis that oxidative imbalance observed in AD could be due to a decreased TAC.     

Microbleeds relate to altered amyloid-beta metabolism in Alzheimer's disease

Cerebral microbleeds (MBs) may relate to amyloid in dementia. We selected 26 probable Alzheimer's disease (AD) patients with MBs, 26 age- and sex-matched AD patients without MBs, 11 vascular dementia (VaD) patients, and 22 patients with subjective complaints. We measured amyloid beta 1-42 (Aβ42) and 1-40 (Aβ40) in cerebrospinal fluid (CSF) and plasma, and blood-brain barrier (BBB) function using albumin ratios. CSF Aβ42 was lowest in AD with MBs, whereas Aβ40 was selectively decreased in VaD. In plasma, amyloid-beta was nonsignificantly elevated in VaD compared with controls. Higher albumin ratios in VaD suggested blood-brain barrier dysfunction. A MB pattern suggestive of cerebral amyloid angiopathy (CAA) related to lower CSF Aβ42, while a non-cerebral amyloid angiopathy specific MB distribution related to higher plasma Aβ40. Amyloid-beta is differentially implicated in AD with MBs and VaD. MB distribution related to different amyloid profiles, supporting distinct etiologies. Our results suggest that Aβ42 is retained in cerebrovasculature of AD patients with MBs, while in contrast, VaD patients may possibly drain amyloid.     

Quantitative functional imaging of the brain: towards mapping neuronal activity by BOLD fMRI.

Quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS) measurements of energy metabolism (i.e. cerebral metabolic rate of oxygen consumption, CMR(O2)), blood circulation (i.e. cerebral blood flow, CBF, and volume, CBV), and functional MRI (fMRI) signal over a wide range of neuronal activity and pharmacological treatments are used to interpret the neurophysiologic basis of blood oxygenation level dependent (BOLD) image-contrast at 7 T in glutamatergic neurons of rat cerebral cortex. Multi-modal MRI and MRS measurements of CMR(O2), CBF, CBV and BOLD signal (both gradient-echo and spin-echo) are used to interpret the neuroenergetic basis of BOLD image-contrast. Since each parameter that can influence the BOLD image-contrast is measured quantitatively and separately, multi-modal measurements of changes in CMR(O2), CBF, CBV, BOLD fMRI signal allow calibration and validation of the BOLD image-contrast. Good agreement between changes in CMR(O2) calculated from BOLD theory and measured by (13)C MRS, reveals that BOLD fMRI signal-changes at 7 T are closely linked with alterations in neuronal glucose oxidation, both for activation and deactivation paradigms. To determine the neurochemical basis of BOLD, pharmacological treatment with lamotrigine, which is a neuronal voltage-dependent Na(+) channel blocker and neurotransmitter glutamate release inhibitor, is used in a rat forepaw stimulation model. Attenuation of the functional changes in CBF and BOLD with lamotrigine reveals that the fMRI signal is associated with release of glutamate from neurons, which is consistent with a link between neurotransmitter cycling and energy metabolism. Comparisons of CMR(O2) and CBF over a wide dynamic range of neuronal activity provide insight into the regulation of energy metabolism and oxygen delivery in the cerebral cortex. The current results reveal the energetic and physiologic components of the BOLD fMRI signal and indicate the required steps towards mapping neuronal activity quantitatively by fMRI at steady-state. Consequences of these results from rat brain for similar calibrated BOLD fMRI studies in the human brain are discussed.     

多层螺旋CT灌注成像对脑肿瘤瘤周水肿的临床应用

目的探讨瘤周水肿的多层螺旋cT灌注成像（CTPI）在脑肿瘤诊断方面的应用价值。方法采用Sensation16层螺旋CT机对本院29例脑肿瘤患者（胶质瘤14例，转移瘤7例，脑膜瘤8例）行CTPI，分别测量不同瘤周水肿区以及对侧正常脑组织的脑血流量（CBF）、脑血容量（CBV）、肿瘤表面渗透性（PS）、对比剂峰值时间（timetopeak，TIP，并进行比较。结果转移瘤和脑膜瘤瘤周水肿的CBV、CBF显著低于对侧正常脑组织（P〈0．05），PS差异则无统计学意义（P〉0．05）。与对侧正常脑组织比较，胶质瘤瘤周水肿的CBV差异无统计学意义（P〉0．05），而PS明显升高（P〈0．05），CBF降低（P〈0．05）。胶质瘤、转移瘤及脑膜瘤3者瘤周水肿的TTP值均较对侧正常脑组织显著延长（P〈0．05）。结论脑肿瘤的CTPI检查能定量反映瘤周水肿区的血流动力学状况，对脑肿瘤的鉴别和预测预后有重要临床意义。     

Principal neuron spiking: neither necessary nor sufficient for cerebral blood flow in rat cerebellum

Neuronal activity, cerebral blood flow, and metabolic responses are all strongly coupled, although the mechanisms behind the coupling remain unclear. One of the key questions is whether or not increases in spiking activity in the stimulated neurons are sufficient to drive the activity-dependent rises in cerebral blood flow (CBF) that form the basis of the signals used in functional neuroimaging such as the blood oxygen level-dependent (BOLD) signal. To this end the present study examined the effect of enhanced spike activity per se on CBF in rat cerebellar cortex under conditions of disinhibition, achieved by blocking GABA_A receptors using either bicuculline or picrotoxin. Purkinje cell spiking activity and local field potentials were recorded by glass microelectrodes, and laser Doppler flowmetry was used to monitor CBF. Disinhibition increased Purkinje cell spiking rate to 200–300% of control without incurring any increase in basal CBF. This demonstrates that increased spike activity per se is not sufficient to affect basal CBF. The neurovascular coupling between excitatory synaptic activity and CBF responses evoked by inferior olive (climbing fibre) stimulation was preserved during disinhibition. Thus, the unchanged basal CBF in the presence of the dramatic rise in Purkinje cell spiking rate was not explained by impaired synaptic activity–CBF coupling. On the basis of our previous and the present studies, we conclude that increased spiking activity of principal neurons is neither sufficient nor necessary to elicit CBF responses and in turn BOLD signals, and that activation-dependent vascular signals reflect excitatory synaptic activity.     

Coupling between cerebral blood flow and cerebral blood volume: Contributions of different vascular compartments

A better understanding of the coupling between changes in cerebral blood flow (CBF) and cerebral blood volume (CBV) is vital for furthering our understanding of the BOLD response. The aim of this study was to measure CBF‐CBV coupling in different vascular compartments during neural activation. Three haemodynamic parameters were measured during a visual stimulus. Look‐Locker flow‐sensitive alternating inversion recovery was used to measure changes in CBF and arterial CBV (CBV_a) using sequence parameters optimized for each contrast. Changes in total CBV (CBV_tot) were measured using a gadolinium‐based contrast agent technique. Haemodynamic changes were extracted from a region of interest based on voxels that were activated in the CBF experiments. The CBF‐CBV_tot coupling constant α_tot was measured as 0.16 ± 0.14 and the CBF‐CBV_a coupling constant α_a was measured as 0.65 ± 0.24. Using a two‐compartment model of the vasculature (arterial and venous), the change in venous CBV (CBV_v) was predicted for an assumed value of baseline arterial and venous blood volume. These results will enhance the accuracy and reliability of applications that rely on models of the BOLD response, such as calibrated BOLD.     

The capillary dysfunction hypothesis of Alzheimer's disease

It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer's disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity.     

Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer's disease

Epidemiologic evidence and postmortem studies of cerebral amyloid angiopathy suggest that vascular dysfunction may play an important role in the pathogenesis of Alzheimer's disease (AD). However, alterations in vascular function under in vivo conditions are poorly understood. In this study, we assessed cerebrovascular-reactivity (CVR) in AD patients and age-matched controls using CO₂-inhalation while simultaneously acquiring Blood-Oxygenation-Level-Dependent (BOLD) MR images. Compared with controls, AD patients had widespread reduction in CVR in the rostral brain including prefrontal, anterior cingulate, and insular cortex (p < 0.01). The deficits could not be explained by cardiovascular risk factors. The spatial distribution of the CVR deficits differed drastically from the regions of cerebral blood flow (CBF) deficits, which were found in temporal and parietal cortices. Individuals with greater CVR deficit tended to have a greater volume of leukoaraiosis as seen on FLAIR MRI (p = 0.004). Our data suggest that early AD subjects have evidence of significant forebrain vascular contractility deficits. The localization, while differing from CBF findings, appears to be spatially similar to PIB amyloid imaging findings.     

Measurements of cerebral blood flow and metabolism in patients with Alzheimer's disease

Positron emission tomography (PET) was used to measure cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and cerebral metabolic rate of glucose (CMRglc) in patients with Alzheimer's disease. In the patients, values for CBF, CMRO2, and CMRglc have been shown to drop by 30-50% in comparison to age-matched normal controls. In the early stage (stage I), reductions in CBF and CMRO2 are prominent in the temporal and the temporoparietal cortices. In stage II, reduction in the parietal cortex also become quite prominent, and in the late stage (stage III) reduction begins prominently in the frontal cortex as well. These PET findings in Alzheimer's disease differ from those in vascular dementia, Pick's disease, and Huntington's disease. In the interrelationship among CBF, CMRO2 and higher brain function, CBF and CMRO2 decrease especially in the left frontal, the left temporal and the left parietal cortices in patients with marked language disability. On the contrary, CBF and CMRO2 decrease in the right temporal and the right parietal cortices in patients with marked apraxia and visuospatial deficits. Cerebral blood flow and metabolism are closely related to the functioning of nerve cells. Therefore we can isolate the region responsible for higher brain dysfunction and similarly evaluate the effects of treatment using cerebral blood flow and metabolism measurements.     

Alzheimer's disease and the 'ABSENT' hypothesis: mechanism for amyloid beta endothelial and neuronal toxicity

Alzheimer's disease [AD] is the most common cause of dementia among people age 65 and older. One of the biggest stumbling blocks in developing effective drug therapy for Alzheimer's disease has been the lack of a comprehensive hypothesis that explains the mechanism behind all of the histopathological changes seen in patients suffering from Alzheimer's disease. An overview of the currently popular 'amyloid' and 'vascular' hypotheses for AD demonstrates that neither hypothesis by itself can explain all the known histopathological and biochemical lesions seen in Alzheimer's disease. The paper presents a hypothesis that tries to explain the mechanism behind almost all the histopathological changes, and varying clinical manifestations seen in both diagnosed AD and Vascular Dementia [VaD]. The new hypothesis is based on the known dual toxicity of beta amyloid to both vascular and neuronal tissues, their synergy and the resultant net effect on the onset and progression of AD. The new hypothesis therefore will be known as the Amyloid Beta Synergistic Endothelial and Neuronal Toxicity [ABSENT] hypothesis. The ABSENT hypothesis will try to show the common chemical mechanism behind almost all of the pathological changes seen in AD. According to the ABSENT hypothesis, beta amyloid itself generates all the free radicals that cause both vascular dysfunction and the neuronal damage seen in AD. The chemical mechanism proposed is based on evidence from physical chemistry experiments, calculations as well as in vitro/in vivo experiments. The ABSENT hypothesis does not favor one mode of beta amyloid-induced brain damage over the other, rather it considers the net effects of the neuronal stress/damage caused by both the cerebrovascular dysfunction and direct neurotoxicity caused by beta amyloid. The hypothesis states that each patient has a different balance of predisposing factors that modulate the extent of neurotoxicity and cerebrovascular dysfunction caused by beta amyloid and thereby explains the wide range and mixed nature of damage and dysfunction seen in the studies done on patients diagnosed with AD, VaD or 'mixed dementias'. According to the hypothesis, beta amyloid peptides are necessary if not sufficient to cause AD, VaD and mixed senile dementias. The hypothesis, therefore, proposes the term Beta Amyloid Dementias [BAD] to describe the conditions currently covered by the diagnoses of 'AD', 'VaD' and 'Mixed [senile] Dementias'. Finally, the ABSENT hypothesis tries to put forth a direct chemical mechanism behind the apparent synergy and increased association between old age, pre- and coexisting vascular disease, diabetes and AD.     

Are Alzheimer's disease, hypertension, and cerebrocapillary damage related?

Alzheimer's disease (AD) patients are often subject to vascular dysfunction besides their specific CNS pathology, which warrants further examination of the interaction between vascular factors and the development of dementia. The association of decreased cerebral blood flow (CBF) or hypertension with AD has been a target of growing interest. Parallel with physiological changes, the cerebral capillaries in AD are also prone to degenerative processes. The microvascular abnormalities that are the result of such degeneration may be the morphological correlates of the vascular pathophysiology pointing to a compromised nutrient transport through the capillaries. Animal models have been developed to study the consequences of hypertension and reduced CBF. Spontaneously hypertensive rats are widely used in hypertension research whereas ligation of the carotid arteries has become a method to produce cerebral hypoperfusion. Based on these models, we propose a relationship between hypertension, cerebral hypoperfusion, cerebral capillary malformation and cognitive decline as it occurs in AD. We suggest that the above conditions are functionally related and can contribute to the progression of AD.     

Modeling dynamic cerebral blood volume changes during brain activation on the basis of the blood-nulled functional MRI signal

Recently, vascular space occupancy (VASO) based functional magnetic resonance imaging (fMRI) was proposed to detect dynamic cerebral blood volume (CBV) changes using the blood-nulled non-selective inversion recovery (NSIR) sequence. However, directly mapping the dynamic CBV change by the NSIR signal change is based on the assumption of slow water exchange (SWE) around the capillary regime without cerebral blood flow (CBF) effects. In the present study, a fast water exchange (FWE) model incorporating with flow effects was derived from the Bloch equations and implemented for the quantification of dynamic CBV changes using VASO-fMRI during brain activation. Simulated results showed that only subtle differences in CBV changes estimated by these two models were observed on the basis of previously published VASO results. The influence of related physiological and biophysical factors within typical ranges was evaluated in steady-state simulations. It was revealed that in the transient state the CBV curves could be delayed in comparison with measured NSIR curves owing to the imbalance between the inflowing and outflowing blood signals.