Harry V. Vinters

Astrocytes: biology and pathology.

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors.

Alzheimers disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either Lxrα or Lxrβ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid β peptide (fAβ) in a receptor-dependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fAβ-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.

Neuropathological basis of magnetic resonance images in aging and dementia

Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present.

Cognitive impact of subcortical vascular and Alzheimer's disease pathology

To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimers disease [AD]), cognitive status, and apolipoprotein E genotype.

Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier

Background Monocyte/macrophages are known to infiltrate the brain of patients with HIV‐1 encephalitis (HIVE). In Alzheimer’s disease brain, the origin of activated microglia has not been determined.

Neuropathologic findings in cortical resections (including hemispherectomies) performed for the treatment of intractable childhood epilepsy

SummaryDespitè the use of hemispherectomy in the treatment of medically refractory seizures since the early 1950s, few studies published have documented neuropathologic findings in the resected specimens. This report describes the neuropathologic findings in 38 children who underwent either hemispherectomy or multilobar cortical resection as treatment for medically intractable epilepsy between 1986 and 1990. Examination of the resected specimens revealed a variety of abnormalities which fell into four broad categories. Malformations or hamartomatous lesions were the dominant finding in 15 patients, whereas encephalomalacic lesions were the most prominent abnormality in 16; chronic pathogen-free encephalitis (Rasmussens encephalitis) was present in 3 and an additional 3 children had Sturge-Weber-Dimitri syndrome. There were no gross or microscopic abnormalities in 1 patient. This report provides the first comprehensive description of the pathologic findings in a series of children with refractory epilepsy of varying types treated by hemispherectomy-multilobar resection.

Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia

The cornu ammonis 1 region of the hippocampus (CA1) sector of hippocampus is vulnerable to both Alzheimers disease (AD)‐type neurofibrillary degeneration and anoxia–ischemia. The objective of this article is to compare number and size of neurons in CA1 in AD versus ischemic vascular dementia. Unbiased stereological methods were used to estimate the number and volume of neurons in 28 autopsy‐derived brain samples. For each case, the entire hippocampus from one cerebral hemisphere was sliced into 5mm slabs (5–7 slabs/case), cut into 50μm sections, and stained with gallocyanine. Using the optical dissector, we systematically sampled the number and size of neurons throughout the extent of CA1 and CA2. The total number of neurons was significantly less in AD compared with ischemic vascular dementia (p < 0.02), but there was no significant difference in neuron size. The greatest loss of neurons was observed in two cases with combined AD and hippocampal sclerosis. Regardless of causative diagnosis, the number of CA1 neurons correlates with magnetic resonance imaging–derived hippocampal volume (r = 0.72; p < 0.001) and memory score (r = 0.62; p < 0.01). We conclude that although CA1 neuron loss is more consistently observed in AD than ischemic vascular dementia, severity of loss shows the expected correlation with structure and function across causative subtype. Reductions in magnetic resonance imaging–derived hippocampal volume reflect loss, rather than shrinkage, of CA1 neurons. Ann Neurol 2005;57:896–903

Brain Parenchymal and Microvascular Amyloid in Alzheimer's Disease

Brains of patients with Alzheimer disease/senile dementia of Alzheimer type (AD/SDAT) develop a progressive accumulation of amyloid, which deposits primarily in the form of characteristic parenchyma!‘plaques’ (senile or neuritic plaques/SPs) and as mural deposits in the walls of capillaries and arterioles (cerebral amyloid angiopa‐thy/CAA). A major component of this amyloid is a small and unique peptide composed of 39–43 amino acids, beta/A4, which is cleaved from a much larger precursor protein (APP) that has several isoforms. Brain amyloid can be detected in autopsy or biopsy brain tissue by classical, immunohistochemical and ultrastructural (including immuno‐electron microscopic) methods of varying sensitivity and specificity. Beta/A4 amyloid deposition is remarkably variable (e.g. predominantly parenchyma! or vascular, or a mixture of parenchymal and vascular) among patients with AD/SDAT. Despite its abundance in the brains of AD/SDAT patients, the precise role of beta/A4 in the pathogenesis of the neurological deficit, neocortical atrophy and progressive synapse loss associated with AD/SDAT has yet to be determined. However, mutations in the gene that encodes APP are clearly associated with familial AD syndromes in which there is significant brain amyloid deposition. CAA, in addition to its association with AD/SDAT, can result in hemorrhagic and (possibly) ischemic forms of stroke. Work with recently developed transgenic mice which express large amounts of beta/A4 in the central nervous system is likely to elucidate mechanisms by which the protein is selectively deposited in the brain in a parenchymal or microvascular form, and how it contributes to the pathogenesis of neurodegeneration.

Hemispherectomy for intractable seizures in children: a report of 58 cases

Fifty-eight children who underwent anatomical, functional, or modified anatomical hemispherectomy for intractable seizures from 1986 to 1995 were evaluated for seizure control, motor function, and complications. Age at surgery ranged from 0.3 to 17.3 years (median 2.8 years). Twenty-seven anatomical, 27 functional, and 4 modified anatomical hemispherectomies were performed. Seizure control and motor function in the 50 patients with more than 1 year follow-up revealed a 90% or better reduction in seizure frequency in 44/50 (88%) overall: 19/22 (86%) anatomical, 23/26 (89%) functional, and 2/2 modified anatomical. Motor function of the preoperatively hemiparetic extremities was improved or unchanged postoperatively in 38/50 (76%) of the patients. Complications included one intraoperative death, one late death from shunt obstruction managed elsewhere, late postoperative seizure breakthrough requiring reoperation and further disconnection in 5/27 functional hemispherectomy patients, mild cerebrospinal fluid infections in 3/27 anatomical hemispherectomy patients, and hydrocephalus requiring shunting in 3/27 functional hemispherectomy patients. A review of the literature and comparison of techniques is presented.

Neurodevelopmental disorders as a cause of seizures: Neuropathologic, genetic, and mechanistic considerations

This review will consider patterns of developmental neuropathologic abnormalities—malformations of cortical development (MCD)—encountered in infants (often with infantile spasms), children, and adults with intractable epilepsy. Treatment of epilepsy associated with some MCD, such as focal cortical dysplasia and tubers of tuberous sclerosis, may include cortical resection performed to remove the “dysplastic” region of cortex. In extreme situations (eg, hemimegalencephaly), hemispherectomy may be carried out on selected patients. Neuropathologic (including immunohistochemical) findings within these lesions will be considered. Other conditions that cause intractable epilepsy and often mental retardation, yet are not necessarily amenable to surgical treatment (eg, lissencephaly, periventricular nodular heterotopia, double cortex syndrome) will be discussed. Over the past 10 years there has been an explosion of information on the genetics of MCD. The genes responsible for many MCD (eg, TSC1, TSC2, LIS‐1, DCX, FLN1) have been cloned and permit important mechanistic studies to be carried out with the purpose of understanding how mutations within these genes result in abnormal cortical cytoarchitecture and anomalous neuroglial differentiation. Finally, novel techniques allowing for analysis of patterns of gene expression within single cells, including neurons, is likely to provide answers to the most vexing and important question about these lesions: Why are they epileptogenic?