Joel B. Kirkpatrick

Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain

Senile plaques found in the brains of patients with Alzheimers disease (AD) are surrounded by clusters of reactive microglia. Isolated human microglia placed in contact with plaques in vitro are activated to release a factor which is toxic to neurons. This same neurotoxin is found in AD brain tissue and causes damage to pyramidal neurons in vivo when infused into rat hippocampus. Highest concentrations of the neurotoxin are in those brain structures most burdened by reactive microglia, suggesting that plaque-activated cells contribute to the neuronal damage and impaired cognition seen in patients with Alzheimers dementia.

The HHQK domain of beta-amyloid provides a structural basis for the immunopathology of Alzheimer's disease.

The β-amyloid peptide 1–42 (Aβ1–42), a major component of neuritic and core plaques found in Alzheimer’s disease, activates microglia to kill neurons. Selective modifications of amino acids near the N terminus of Aβ showed that residues 13–16, the HHQK domain, bind to microglial cells. This same cluster of basic amino acids is also known as a domain with high binding affinity for heparan sulfate. Both Aβ binding to microglia and Aβ induction of microglial killing of neurons were sensitive to heparitinase cleavage and to competition with heparan sulfate, suggesting membrane-associated heparan sulfate mediated plaque-microglia interactions through the HHQK domain. Importantly, small peptides containing HHQK inhibited Aβ1–42 cell binding as well as plaque induction of neurotoxicity in human microglia. In vivo experiments confirmed that the HHQK peptide reduces rat brain inflammation elicited after infusion of Aβ peptides or implantation of native plaque fragments. Strategies which exploit HHQK-like agents may offer a specific therapy to block plaque-induced microgliosis and, in this way, slow the neuronal loss and dementia of Alzheimer’s disease.

Trigeminal neuralgia and multiple sclerosis: demonstration of the plaque in an operative case

Trigeminal neuralgia is unique to humans. The most common cause seems to be an injury to the myelin of the trigeminal nerve root entry zone as it extends for several millimeters lateral to the pons. Jannetta has developed an elegant retromastoid microsurgical approach to this region. He has identified a compression-distortion phenomenon of this nerve root entry zone, usually from an anomalous position of the superior cerebella artery. Trigeminal neuralgia can also occur in association with multiple sclerosis, when the plaque lies in this same location. The historical evidence for this explanation is reinforced by the electron microscopic demonstration of the plaque in this region in a patient with multiple sclerosis who was suffering from tic douloureux. (Neurosurgery, 5: 711--717, 1979).

Immunohistochemical Demonstration of Neuronal and Astrocytic Differentiation in Retinoblastoma

Sections of 51 surgically enucleated eyes from cases of retinoblastomas were examined immunohistochemically to delineate patterns of cellular differentiation. Employing the avidin-biotin immunoperoxidase technique, antibodies were used against glial fibrillary acidic protein (GFAP), S-100 protein and neuron specific enolase (NSE). Areas of uninvolved retina and/or optic nerve were used as built-in positive control. Most of the tumors showed GFAP and S-100 protein-positive perivascular glial cells that were interpreted as reactive astrocytes. In three well-differentiated retinoblastomas, glial cells were found to be interspersed randomly among tumor cells and not associated with blood vessels. These glial cells were interpreted as neoplastic based on their distribution pattern and cytologic features. In about half of the tumors, the retinoblastoma cells stained positively for NSE, indicating their neuronal tumor cells that stained positively for NSE but failed to show any evidence of photoreceptor differentiation. Based on these observations and similar differentiation patterns described in other primitive neuroectodermal tumors of the brain, it is suggested that retinoblastoma cells can differentiate not only into photoreceptor cells but also along other neuronal cell lines and rarely into glial cells.

Cavernous sinus syndrome as the presentation of malignant lymphoma: Case report and review of the literature

Cavernous sinus syndrome (CSS) is an unusual presentation of malignant lymphoma. We report a patient with lymphoma that presented with CSS, and we review the literature on nine other reported cases. Sharp retroorbital pain, paraesthesia around the orbit, and complete 6th nerve palsy were dominant presenting symptoms. In all cases, the tumor developed on the right side. The computed tomographic scan was abnormal in only two of the nine patients during the early stages of the disease. The dominant histological type was large cell lymphoma. The mean age of the patients was 45 years. The mean survival time after the first presenting symptom was 8.7 months. Two of the reported patients as well as our patient had disseminated disease, which became evident at autopsy.

Distribution of elements in rat peripheral axons and nerve cell bodies determined by X-ray microprobe analysis

Abstract: X‐ray microprobe analysis was used to determine concentrations (millimoles of element per kilogram dry weight) of Na, P, Cl, K, and Ca in cellular compartments of frozen, unfixed sections of rat sciatic and tibial nerves and dorsal root ganglion (DRG). Five compartments were examined in peripheral nerve (axoplasm, mitochondria, my‐elin, extraaxonal space, and Schwann cell cytoplasm), and four were analyzed in DRG nerve cell bodies (cytoplasm, mitochondria, nucleus, and nucleolus). Each morphological compartment exhibited characteristic concentrations of elements. The extraaxonal space contained high concentrations of Na, Cl, and Ca, whereas intraaxonal compartments exhibited lower concentrations of these elements but relatively high K. contents. Nerve axoplasm and axonal mitochondria had similar elemental profiles, and both compartments displayed proximodistal gradients of decreasing levels of K, Cl, and, to some extent, Na. Myelin had a selectively high P concentration with low levels of other elements. The elemental concentrations of Schwann cell cytoplasm and DRG were similar, but both were different from that of axoplasm, in that K and Cl were markedly lower whereas P was higher. DRG cell nuclei contained substantially higher K levels than cytoplasm. The subcellu‐lar distribution of elements was clearly shown by color‐coded images generated by computer‐directed digital x‐ray imaging. The results of this study demonstrate characteristic elemental distributions for each anatomical compartment, which doubtless reflect nerve cell structure and function.

Neuropathology of two fatal cases of measles in the 1988-1989 Houston epidemic.

The clinical course and autopsy findings of 2 patients with measles encephalitis that occurred during the 1988-1989 Houston epidemic are reported. A previously healthy 25-month-old boy had serologically-proved measles, hemophagocytic syndrome, and acute disseminated demyelinating encephalitis. A 19-year-old male with acute lymphocytic leukemia had proved measles pneumonia and acute hemorrhagic leukoencephalitis. These patients represent a broad spectrum of measles-induced immunopathic complications of the central nervous system.

In vitro Simulation of Neural Trauma by Laser

A serious lack of knowledge about central nervous system trauma is encountered on the cellular level where the inability to create precise experimental lesions of known magnitude has limited our understanding of the reactions of single cells to injury. We used a laser cell surgery technique developed in this laboratory to manipulate neurons in a controlled environment, in order to observe pathologic reactions during and immediately after the injury. This technique is especially suited for axonal and dendritic amputations close to the perikaryon. The laser provided three different physical modes of injury to neurites: direct vaporization of cytoplasm, pressure wave damage from external vaporization of substrate material, and photobiologically-induced localized cytoskeletal destruction leading to the slow pinching of processes followed by transection. Our data indicated a great similarity between laser impact damage and the cellular damage produced by physical trauma to the central nervous system.

Temporal changes in red blood cell hydration: application to MRI of hemorrhage

It has been established that red blood cell (RBC) dehydration causes significant changes in MRI signal intensity by decreasing both the T1 and T2 relaxation times. This study was conducted to determine if these changes occurred in blood clots maintained at body temperature for times ranging from 15 min to 10 days. Venous blood was used to form clots which were stored at 37°C. The shape and diameter of 20–50 RBCs were measured in the fresh and fixed states. By 12–48 h after clot formation virtually all RBCs lost their biconcave shape and became spherical echinocytes. The volume of these cells decreased by at least 15% over the next 72 h. This change indicates a decrease in the fraction of the cell weight occupied by water of 0.05, which is large enough to alter MR signal intensity significantly. The authors conclude that dehydration of RBCs occurs in vitro within an aging clot. If these changes occur in vivo they should cause a significant decrease in signal intensity on long TR/TE (T2-weighted) images.