Age-related microvascular degeneration in the human cerebral periventricular white matter

Clinical studies have identified white matter (WM) lesions as hyperintensive regions in the MRI images of elderly patients. Since a cerebrovascular origin was attributed to such lesions, the present analysis set out to define the microvascular histopathologic changes in the periventricular WM in the aged. Post-mortem samples of the frontal, parietal, and occipital periventricular WM of 40-90-year-old subjects were prepared for quantitative light and electron microscopy. Light microscopic examination revealed microvascular fibrohyalinosis as the most common type of microvascular damage in the elderly. Ultrastructural analysis identified the microvascular thickening as collagen deposits affecting the basement membrane. The vascular density did not correlate with the age. The basement membrane pathology significantly increased, while the number of intact microvessels gradually decreased, with advancing age in the frontal and occipital WM. Finally, peripheral atherosclerosis coincided with massive microvascular fibrosis, particularly in the frontal WM. Our results demonstrate an age-related microvascular degeneration in the periventricular WM, which may contribute to the development of WM lesions by hindering a sufficient supply of nutrients to the affected WM sites. Furthermore, the data accord with previous observations identifying the frontal lobe as the site at which WM vulnerability is most pronounced. Finally, atherosclerosis in large, peripheral vessels is considered to be a predictive marker of microvascular pathology in the WM.</p

Similar Ultrastructural Breakdown of Cerebrocortical Capillaries in Alzheimer’s Disease, Parkinson’s Disease, and Experimental Hypertension. What is the Functional Link?

The brain, as an intensely active organ, is highly dependent on a sufficient nutrient and oxygen availability in order to reach its optimal working capacity. It is well known that the vital supply of energy substrates is provided by the circulatory system, which splits up into a fine, terminal capillary network in target tissues. These capillaries are considered as important sites, since the actual nutrient trafficking takes place through their walls. That is why an intact, preserved structure of the microvessels is crucial to fulfill their function. Since the brain is known to be particularly vulnerable to suboptimal oxygen and glucose delivery, the intact morphology of capillaries is of paramount importance. Several observations have indicated that the cerebral capillary ultrastructure is damaged in Alzheimer’s disease (AD). Curiously, the regional cerebral blood flow of AD patients is also significantly lower than in age-matched control individuals. Based on these data, it has been suggested that the decreased blood supply and the cerebrovascular alterations contribute to the development of dementia. However, we have observed similar capillary damage in Parkinson’s disease patients and chronically hypertensive rats in addition to AD cases, as presented here. These findings indicate that cerebral capillary damage is not exclusive for AD but occurs under other neurodegenerative disorders and hypertension, as well. We hypothesize that ultrastructural abnormalities of cerebral capillaries are causally related to decreased cerebral blood flow and create a condition that favors neurodegenerative mechanisms including the development of dementia

Pharmacokinetic Analysis of Gd-DTPA Enhancement in dynamic three-dimensional MRI of breast lesions

The purpose of this study was to demonstrate that dynamic MRI covering both breasts can provide sensitivity for tumor detection as well as specificity and sensitivity for differentiation of tumor malignancy. Three-dimensional gradient echo scans were used covering both breasts. Before Gd-DTPA bolus injection, two scans were obtained with different flip angles, and after injection, a dynamic series followed. Thirty-two patients were scanned according to this protocol. From these scans, in addition to enhancement, the value of T1 before injection was obtained. This was used to estimate the concentration of Gd-DTPA as well as the pharmacokinetic parameters governing its time course. Signal enhancement in three-dimensional dynamic scanning was shown to be a sensitive basis for detection of tumors. In our series, all but two mam-mographically suspicious lesions did enhance, and in three cases, additional enhancing lesions were found, two of which were in the contralateral breast. The parameter most suited for classification of breast lesions into benign or malignant was shown to be the pharmacokinetically defined permeability k31, which, for that test, gave a sensitivity of 92% and a specificity of 70%. Our three-dimensional dynamic MRI data are sensitive for detection of mammographically occult breast tumors and specific for classification of these as benign or malignant

Polarised Asymmetric Inheritance of Accumulated Protein Damage in Higher Eukaryotes

Disease-associated misfolded proteins or proteins damaged due to cellular stress are generally disposed via the cellular protein quality-control system. However, under saturating conditions, misfolded proteins will aggregate. In higher eukaryotes, these aggregates can be transported to accumulate in aggresomes at the microtubule organizing center. The fate of cells that contain aggresomes is currently unknown. Here we report that cells that have formed aggresomes can undergo normal mitosis. As a result, the aggregated proteins are asymmetrically distributed to one of the daughter cells, leaving the other daughter free of accumulated protein damage. Using both epithelial crypts of the small intestine of patients with a protein folding disease and Drosophila melanogaster neural precursor cells as models, we found that the inheritance of protein aggregates during mitosis occurs with a fixed polarity indicative of a mechanism to preserve the long-lived progeny

Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain

Though cerebral white matter injury is a frequently described phenomenon in aging and dementia, the cause of white matter lesions has not been conclusively determined. Since the lesions are often associated with cerebrovascular risk factors, ischemia emerges as a potential condition for the development of white matter injury. In the present study, we induced experimental cerebral hypoperfusion by permanent, bilateral occlusion of the common carotid arteries of rats (n=6). A sham-operated group served as control (n=6). Thirteen weeks after the onset of occlusion, markers for astrocytes, microglia, and myelin were found to be labeled by means of immunocytochemistry in the corpus callosum, the internal capsule, and the optic tract. The ultrastructural integrity and oligodendrocyte density in the optic tract were investigated by electron microscopy. Quantitative analysis revealed that chronic cerebral hypoperfusion caused mild astrogliosis in the corpus callosum and the internal capsule, while astrocytic disintegration in the optic tract increased by 50%. Further, a ten-fold increase in microglial activation and a nearly doubled oligodendrocyte density were measured in the optic tract of the hypoperfused rats as compared with the controls. Finally, vacuolization and irregular myelin sheaths were observed at the ultrastructural level in the optic tract. In summary, the rat optic tract appears to be particularly vulnerable to ischemia, probably because of the rat brain’s angioarchitecture. Since the detected glial changes correspond with those reported in vascular and Alzheimer dementia, this model of cerebral hypoperfusion may serve to characterize the causal relationship between ischemia and white matter damage.

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.

Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease

Cerebral capillaries represent a major interface between the general circulation and the central nervous system and are responsible for sufficient and selective nutrient transport to the brain. Structural damage or dysfunctioning carrier systems of such an active barrier leads to compromised nutrient trafficking. Subsequently, a decreased nutrient availability in the neural tissue may contribute to hampered neuronal metabolism, hence to behavioral and cognitive functional deficiencies. Here we focus on the ultrastrucutral abnormalities of cerebral microvessels in Alzheimer’s disease (AD; n = 5) and Parkinson’s diseasse (PD; n = 10). The capillary microanatomy in samples from the cingulate cortex was investigated by electron microscopy and severe damage to the vessel walls was observed. Characteristic pathological changes including capillary basement membrane thickening and collagen accumulation in the basement membrane were enhanced in both AD and PD. The incidence of capillaries with basement membrane deposits was two times higher in AD and PD than in age-matched controls. Degenerative pericytes in all groups appeared at a similar frequency. The data indicate that basement membrane deposists, as opposed to pericytic degeneration, represent an important pathological feature of AD and PD and suggest that capillary dysfunction may play a causal role in the development of these two major neurodegenerative diseases.

Age-related microvascular degeneration in the human cerebral periventricular white matter

Clinical studies have identified white matter (WM) lesions as hyperintensive regions in the MRI images of elderly patients. Since a cerebrovascular origin was attributed to such lesions, the present analysis set out to define the microvascular histopathologic changes in the periventricular WM in the aged. Post-mortem samples of the frontal, parietal, and occipital periventricular WM of 40–90-year-old subjects were prepared for quantitative light and electron microscopy. Light microscopic examination revealed microvascular fibrohyalinosis as the most common type of microvascular damage in the elderly. Ultrastructural analysis identified the microvascular thickening as collagen deposits affecting the basement membrane. The vascular density did not correlate with the age. The basement membrane pathology significantly increased, while the number of intact microvessels gradually decreased, with advancing age in the frontal and occipital WM. Finally, peripheral atherosclerosis coincided with massive microvascular fibrosis, particularly in the frontal WM. Our results demonstrate an age-related microvascular degeneration in the periventricular WM, which may contribute to the development of WM lesions by hindering a sufficient supply of nutrients to the affected WM sites. Furthermore, the data accord with previous observations identifying the frontal lobe as the site at which WM vulnerability is most pronounced. Finally, atherosclerosis in large, peripheral vessels is considered to be a predictive marker of microvascular pathology in the WM.

Biological characterisation of vascular grafts cultured in a bioreactor

In this study, the development is described of a tissue-engineered construct mimicking the structure of a natural blood vessel. Smooth muscle cells (SMC) were cultured under pulsatile flow conditions in porous tubular scaffolds composed of crosslinked type I insoluble collagen and insoluble elastin. Under these dynamic culture conditions, average wall shear rate, systolic and diastolic pressures and pressure wave-forms comparable to conditions in the human carotid artery were obtained. Culturing of SMC in tubular scaffolds under dynamic conditions resulted in enhanced tissue formation compared to static conditions. Higher SMC numbers, a more homogeneous distribution of SMC throughout the scaffolds and higher collagen mRNA expression levels were found when cells were cultured under dynamic compared to static conditions. mRNA expression levels of markers of proliferation and apoptosis showed that the higher cell numbers in the scaffolds cultured under dynamic conditions can be explained by increased cell proliferation but not by decreased apoptosis. Glucose consumption and lactate formation by the cells showed that cell metabolism was more aerobic under dynamic compared to static conditions. Lining of the dynamically cultured constructs with a luminal monolayer of endothelial cells might result in vessels suitable for in vivo applications