Modeling and design of a cone-beam CT head scanner using task-based imaging performance optimization.

Detection of acute intracranial hemorrhage (ICH) is important for diagnosis and treatment of traumatic brain injury, stroke, postoperative bleeding, and other head and neck injuries. This paper details the design and development of a cone-beam CT (CBCT) system developed specifically for the detection of low-contrast ICH in a form suitable for application at the point of care. Recognizing such a low-contrast imaging task to be a major challenge in CBCT, the system design began with a rigorous analysis of task-based detectability including critical aspects of system geometry, hardware configuration, and artifact correction. The imaging performance model described the three-dimensional (3D) noise-equivalent quanta using a cascaded systems model that included the effects of scatter, scatter correction, hardware considerations of complementary metal-oxide semiconductor (CMOS) and flat-panel detectors (FPDs), and digitization bit depth. The performance was analyzed with respect to a low-contrast (40-80 HU), medium-frequency task representing acute ICH detection. The task-based detectability index was computed using a non-prewhitening observer model. The optimization was performed with respect to four major design considerations: (1) system geometry (including source-to-detector distance (SDD) and source-to-axis distance (SAD)); (2) factors related to the x-ray source (including focal spot size, kVp, dose, and tube power); (3) scatter correction and selection of an antiscatter grid; and (4) x-ray detector configuration (including pixel size, additive electronics noise, field of view (FOV), and frame rate, including both CMOS and a-Si:H FPDs). Optimal design choices were also considered with respect to practical constraints and available hardware components. The model was verified in comparison to measurements on a CBCT imaging bench as a function of the numerous design parameters mentioned above. An extended geometry (SAD = 750 mm, SDD = 1100 mm) was found to be advantageous in terms of patient dose (20 mGy) and scatter reduction, while a more isocentric configuration (SAD = 550 mm, SDD = 1000 mm) was found to give a more compact and mechanically favorable configuration with minor tradeoff in detectability. An x-ray source with a 0.6 mm focal spot size provided the best compromise between spatial resolution requirements and x-ray tube power. Use of a modest anti-scatter grid (8:1 GR) at a 20 mGy dose provided slight improvement (~5-10%) in the detectability index, but the benefit was lost at reduced dose. The potential advantages of CMOS detectors over FPDs were quantified, showing that both detectors provided sufficient spatial resolution for ICH detection, while the former provided a potentially superior low-dose performance, and the latter provided the requisite FOV for volumetric imaging in a centered-detector geometry. Task-based imaging performance modeling provides an important starting point for CBCT system design, especially for the challenging task of ICH detection, which is somewhat beyond the capabilities of existing CBCT platforms. The model identifies important tradeoffs in system geometry and hardware configuration, and it supports the development of a dedicated CBCT system for point-of-care application. A prototype suitable for clinical studies is in development based on this analysis.

Task-Based Regularization Design for Detection of Intracranial Hemorrhage in Cone-Beam CT.

Prompt and reliable detection of acute intracranial hemorrhage (ICH) is critical to treatment of a number of neurological disorders. Cone-beam CT (CBCT) systems are potentially suitable for detecting ICH (contrast 40-80 HU, size down to 1 mm) at the point of care but face major challenges in image quality requirements. Statistical reconstruction demonstrates improved noise-resolution tradeoffs in CBCT head imaging, but its capability in improving image quality with respect to the task of ICH detection remains to be fully investigated. Moreover, statistical reconstruction typically exhibits nonuniform spatial resolution and noise characteristics, leading to spatially varying detectability of ICH for a conventional penalty. In this work, we propose a spatially varying penalty design that maximizes detectability of ICH at each location throughout the image. We leverage theoretical analysis of spatial resolution and noise for a penalized weighted least-squares (PWLS) estimator, and employ a task-based imaging performance descriptor in terms of detectability index using a nonprewhitening observer model. Performance prediction was validated using a 3D anthropomorphic head phantom. The proposed penalty achieved superior detectability throughout the head and improved detectability in regions adjacent to the skull base by ~10% compared to a conventional uniform penalty. PWLS reconstruction with the proposed penalty demonstrated excellent visualization of simulated ICH in different regions of the head and provides further support for development of dedicated CBCT head scanning at the point-of-care in the neuro ICU and OR.

Statistical reconstruction for cone-beam CT with a post-artifact-correction noise model: application to high-quality head imaging.

Non-contrast CT reliably detects fresh blood in the brain and is the current front-line imaging modality for intracranial hemorrhage such as that occurring in acute traumatic brain injury (contrast ~40-80 HU, size > 1 mm). We are developing flat-panel detector (FPD) cone-beam CT (CBCT) to facilitate such diagnosis in a low-cost, mobile platform suitable for point-of-care deployment. Such a system may offer benefits in the ICU, urgent care/concussion clinic, ambulance, and sports and military theatres. However, current FPD-CBCT systems face significant challenges that confound low-contrast, soft-tissue imaging. Artifact correction can overcome major sources of bias in FPD-CBCT but imparts noise amplification in filtered backprojection (FBP). Model-based reconstruction improves soft-tissue image quality compared to FBP by leveraging a high-fidelity forward model and image regularization. In this work, we develop a novel penalized weighted least-squares (PWLS) image reconstruction method with a noise model that includes accurate modeling of the noise characteristics associated with the two dominant artifact corrections (scatter and beam-hardening) in CBCT and utilizes modified weights to compensate for noise amplification imparted by each correction. Experiments included real data acquired on a FPD-CBCT test-bench and an anthropomorphic head phantom emulating intra-parenchymal hemorrhage. The proposed PWLS method demonstrated superior noise-resolution tradeoffs in comparison to FBP and PWLS with conventional weights (viz. at matched 0.50 mm spatial resolution, CNR = 11.9 compared to CNR = 5.6 and CNR = 9.9, respectively) and substantially reduced image noise especially in challenging regions such as skull base. The results support the hypothesis that with high-fidelity artifact correction and statistical reconstruction using an accurate post-artifact-correction noise model, FPD-CBCT can achieve image quality allowing reliable detection of intracranial hemorrhage.

Cortical interneurons become activated by deafferentation and instruct the apoptosis of pyramidal neurons.

Unlike peripheral nervous system neurons and certain groups of nerve cells in the CNS, cortical projection neurons are tolerant of axonal lesions. This resistance is incongruent with the massive death of pyramidal neurons in age-associated neurodegenerative diseases that proceed along corticocortical connections. Some insights have emerged from our previous work showing that pyramidal cells in piriform cortex undergo classical apoptosis within 24 h after bulbectomy via transsynaptic, but not retrograde, signaling. These findings allow the investigation of cellular and molecular changes that take place in the context of experimental cortical degeneration. In the present study, we show that the transsynaptic death of pyramidal neurons in piriform cortex is a nitric oxide-mediated event signaled by activated interneurons in layer I. Thus, we demonstrate that cortical interneurons play an essential role in transducing injury to apoptotic signaling that selectively targets pyramidal neurons. We propose that this mechanism may be generic to cortical degenerations and amenable to therapeutic interventions.

Estrogens modulate experimentally induced apoptosis of granule cells in the adult hippocampus.

Estrogens are known to have broad effects on neuronal plasticity, but their specific role in neuronal cell death has not been determined. In the present study, we investigated the effects of beta-estradiol on an experimental model of apoptosis of granule cells of the dentate gyrus, i.e., apoptosis induced by intraventricular injection of the microtubule polymerization inhibitor colchicine. Cell death was characterized with multiple methods, including TUNEL and DNA electrophoresis. Nonrandom digestion of DNA was observed within 8-10 hours after colchicine injection, followed by condensation and fragmentation of granule cell nuclei and extensive anterograde degeneration of mossy fibers/terminals in 2 days. We compared the outcomes of the above-described manipulation in ovariectomized or sham-operated rats and animals treated daily with beta-estradiol or vehicle. Animals were lesioned with colchicine or vehicle 2 weeks after ovariectomy or sham operation. Beta-estradiol or vehicle was administered for 1 week prior to lesion and was continued for a further 2 weeks. Total numbers and densities of granule cells in different animal groups were counted by stereology in various anteroposterior levels of the hippocampus. Our results show that ovariectomy intensifies colchicine-induced granule cell apoptosis, which is ameliorated by exogenous beta-estradiol. In doses that ameliorate the adverse effect of ovariectomy, exogenous beta-estradiol appears to have no effect of preventing granule cell death in animals with intact ovaries; i.e., an estrogen excess is not more neuroprotective than physiological levels of these hormones. Taken together, our results indicate that estrogen deprivation increases the vulnerability of hippocampal neurons to injury and may predispose to neurological diseases occurring after menopause.

Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase.

Genetically engineered mice with targeted disruption of the neuronal nitric oxide synthase (nNOS) gene established the inhibitory role of nitric oxide (NO) in male impulsive aggressive behavior. This was later confirmed by using selective nNOS inhibitors in male wild-type mice. The molecular mechanisms accounting for the aggressive behavior caused by the lack of neuronally derived NO is not known. Recent studies suggest that central serotonergic neuronal circuits and particularly 5-HT(1A) and 5-HT(1B) receptors play a prominent role in the regulation of aggression. Accordingly, we investigated whether the aggressiveness caused by the lack of nNOS might be because of alterations in serotonergic function. We now demonstrate that the excessive aggressiveness and impulsiveness of nNOS knockout mice is caused by selective decrements in serotonin (5-HT) turnover and deficient 5-HT(1A) and 5-HT(1B) receptor function in brain regions regulating emotion. These results indicate an important role for NO in normal brain 5-HT function and may have significant implications for the treatment of psychiatric disorders characterized by aggressiveness and impulsivity.

Nerve growth factor expression and release in allergic inflammatory disease of the upper airways.

It is well known that allergic airways disease is characterized by inflammation and hyperresponsiveness, but the link between these two conditions has not been elucidated. We have previously shown that in allergic rhinitis, hyperresponsiveness is attributable to increased neural reactivity. We thus hypothesized that nerve growth factor (NGF), which is expressed by inflammatory cells and effects changes that lead to increased neural responsiveness, could be a pivotal mediator in this disease. Using reverse transcription-polymerase chain reaction (RT-PCR), Western immunoblotting, and ELISA to evaluate NGF expression and release, we found that subjects with allergic rhinitis have significantly decreased NGF mRNA in superficial nasal scrapings and significantly higher baseline concentrations of NGF protein in nasal lavage fluids, compared with control subjects. Nasal provocation with allergen significantly increased NGF protein in nasal lavage fluids of subjects with allergic rhinitis, but not of control subjects. The concentrations of NGF protein in nasal lavage fluids were not affected by provocation with the vehicle for allergen or with histamine. These data provide the first evidence of a steady state of dysregulation in mucosal NGF expression and release in allergic rhinitis, and support a role of this neurotrophin in the pathophysiology of allergic inflammatory disease of the human airways.

Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities.

Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF(+/-) mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF(+/-) mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF(+/-) mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF(+/-) mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.

Intraventricular infusion of nerve growth factor as the cause of sympathetic fiber sprouting in sensory ganglia.

OBJECT: The results of previous clinical trials have indicated that intraventricular infusion of nerve growth factor (NGF) in patients with Alzheimer's disease is frustrated by the appearance of weight loss and diffuse back pain. The present study tested whether NGF induces sympathetic sprouting in sensory ganglia. Such sprouting has been implicated in previous studies as a possible mechanism of sympathetically maintained pain in neuropathic animals. METHODS: Nineteen Long-Evans rats underwent intraventricular infusion of either artificial cerebrospinal fluid (ACSF; seven animals) or NGF (12 animals). After 14 days of infusion, the sensory ganglia of the trigeminal nerve and the C-2, C-8, T-1, L-4, and L-5 dorsal roots were examined for sympathetic sprouting by using tyrosine hydroxylase immunohistochemical analysis. CONCLUSIONS: In the animals receiving NGF, 52 of 144 ganglia showed sympathetic fiber sprouting. In the control animals receiving ACSF, only two of 72 ganglia showed minor sympathetic fiber sprouting. A preferential sprouting of sympathetic fibers was demonstrated at lower lumbar ganglia compared with the cervical and thoracic ganglia. The data presented here demonstrate that in the rat intraventricular NGF infusion caused sympathetic sprouting in dorsal root ganglia (p < 0.01). These findings may have importance both for the treatment of Alzheimer's disease and the understanding of neuropathic pain.

Neural hyperresponsiveness and nerve growth factor in allergic rhinitis.

BACKGROUND: In allergic rhinitis, symptoms are triggered not only by allergens but also by environmental irritants. Hereinafter we address the hypothesis that this is reflective of increased responsiveness of the neural apparatus which, in turn, may be attributable to upregulation of nerve growth factor (NGF) in this disease. METHODS: We compared subjects with active allergic rhinitis and healthy volunteers in terms of sensitivity and/or magnitude of three nerve-mediated responses, namely (1) the sneezing reflex induced by histamine, (2) the central or nasonasal reflex depicted by contralateral secretions induced by unilateral nasal challenge with capsaicin, and (3) the axonal reflex depicted by plasma extravasation upon capsaicin challenge. We have also measured NGF levels in nasal lavage fluids at baseline and with allergen provocation in rhinitis and healthy subjects. RESULTS: Compared to healthy individuals, subjects with active allergic rhinitis were found to have (1) significantly greater sensitivity and reactivity of the sneezing reflex, (2) significantly greater secretory responsiveness to sensory nerve stimulation, and (3) significantly greater plasma extravasation indicated by albumin leakage following capsaicin nasal challenge. We also found that subjects with active allergic rhinitis have significantly greater baseline levels of NGF in nasal lavage fluids compared to their healthy counterparts, and that these levels can be increased by allergen nasal provocation. CONCLUSION: The responsiveness of the neural apparatus of the nose is significantly greater in patients with active allergic rhinitis. The increased presence of NGF in the nasal mucosa of these patients supports the hypothesis that this neurotrophin may be implicated in neural hyperresponsiveness.

Evidence that nerve growth factor influences recent memory through structural changes in septohippocampal cholinergic neurons.

We compared, in 4- and 23-month-old Fischer-344 rats, the effects of nerve growth factor (NGF) on basal forebrain cholinergic neurons with behavioral performance in acetylcholine-dependent memory tasks (recent and reference memory). Noncholinergic monoamine markers in target fields of cholinergic neurons were also investigated. We found that NGF has contrasting effects on recent memory in the two age groups in causing improvement in aged rats and deterioration in young rats. In addition, NGF caused significant increase in the size of cholinergic perikarya in all sectors of the basal nucleus complex (BNC). Higher doses of NGF were required to produce hypertrophy in aged animals, a pattern consistent with a lower sensitivity to NGF of aged cholinergic neurons. Analysis of covariance showed that the behavioral effects of NGF were eliminated after covarying out the hypertrophy of cholinergic perikarya. Therefore, NGF causes hypertrophy of cholinergic perikarya regardless of age, and this neurobiological measure correlates with the effects of NGF on recent memory. Reference memory improved moderately only in old rats. This mild effect covaried with an increase in choline acetyltransferase activity in neocortex. Cortical terminal fields of noradrenergic and serotoninergic pathways were not affected by NGF. Taken together, our results indicate that NGF influences recent memory in an age- and transmitter-specific fashion. We postulate that the direct cause of the effects of NGF on memory is not perikaryal hypertrophy per se but rather an increased density of terminals, which always accompanies perikaryal hypertrophy. Although these results continue to support the use of NGF for the treatment of Alzheimer's disease, they raise questions regarding the therapeutic role of NGF for degeneration of BNC neurons occurring in young age.

Peripheral nerve grafts exert trophic and tropic effects on anterior thalamic neurons.

Peripheral nerve grafting into the central nervous system (CNS) has been used to study the regenerative capabilities of central neurons given access to a peripheral nervous system (PNS) environment. It is well documented that many CNS neurons regenerate axons along peripheral nerve grafts placed in close proximity to their cell bodies and that these grafts can ameliorate axotomy-induced retrograde degeneration. In the present study, we placed peripheral nerve grafts in proximity to axotomized neurons of the anterior thalamus. Standard histological and retrograde tracing techniques were used to examine these preparations 2 months after grafting. Three effects of these grafts were observed: amelioration of retrograde degeneration of axotomized anterior thalamic neurons, hypertrophy of many thalamic neurons in the local environment of the graft, and ingrowth of axons of axotomized anterior thalamic neurons as well as nonaxotomized neurons from surrounding nuclei. We conclude from these studies that peripheral nerve grafts not only provide a matrix for axonal outgrowth but also exert marked trophic and tropic effects on axotomized anterior thalamic neurons.

Deafferentation causes apoptosis in cortical sensory neurons in the adult rat.

The present study provides an experimental model of the apoptotic death of pyramidal neurons in rat olfactory cortex after total bulbectomy. Terminal transferase (TdT)-mediated deoxyuridine triphosphate (d-UTP)-biotin nick end labeling (TUNEL), DNA electrophoresis, and neuronal ultrastructure were used to provide evidence of apoptosis; neurons in olfactory cortex were counted by stereology. Maximal TUNEL staining occurred in the piriform cortex between 18 and 26 hr postbulbectomy. Within the survival times used in the present study (up to 48 hr postlesion), cell death was observed exclusively in the piriform cortex; there was no evidence of cell death in any other areas connected with the olfactory bulb. Neurons undergoing apoptosis were pyramidal cells receiving inputs from, but not projecting to, the olfactory bulb. The apical dendrites of these neurons were contacted by large numbers of degenerating axonal terminals. Gel electrophoresis of DNA purified from lesioned olfactory cortex showed a ladder pattern of fragmentation. Inflammatory cells or phagocytes were absent in the environment of degenerating neurons in the early stages of the apoptotic process. The present model suggests that deafferentation injury in sensory systems can cause apoptosis. In addition, olfactory bulbectomy can be used for investigating molecular mechanisms that underlie apoptosis in mature mammalian cortical neurons and for evaluating strategies to prevent the degeneration of cortical neurons.

Evidence that perihypoglossal neurons involved in vestibular-auditory and gaze control functions respond to nerve growth factor.

Nerve growth factor (NGF), which has long been considered to be a trophic factor for peripheral sensory and sympathetic neurons, has been found recently to influence cholinergic neurons in the basal forebrain and neostriatum. In the present study, we provide evidence that brainstem neurons in the perihypoglossal area that relay information from the inner ear and vestibular apparatus to the cerebellum and tectum are responsive to NGF. These neurons, which are located in the nucleus prepositus hypoglossi (NPH), spinal vestibular nucleus, cochlear complex, and gigantocellular and paragigantocellular nuclei of the reticular formation, express functional receptors for NGF and up-regulate the expression of trkA receptors after injection of NGF into targets. In addition, the developmental up-regulation of NGF in the cerebellum coincides with the differentiation of the perihypoglossal nuclei. These results suggest that neurons representing the principal brain relays for auditory and vestibular pathways and perihypoglossal neurons involved in gaze coordination are a novel group of central neurons (besides cholinergic neurons in the basal forebrain and neostriatum) that respond to NGF.

The effects of nerve growth factor on spatial recent memory in aged rats persist after discontinuation of treatment.

Nerve growth factor (NGF) infusion significantly reduces spatial recent memory deficits in aged rats, an effect that has great relevance to the treatment of memory impairments characteristic of patients with Alzheimer's disease. The present study was designed to examine whether this NGF-induced improvement in spatial recent memory persists after the discontinuation of NGF treatment, an issue of crucial importance for the potential clinical use of this compound. Spatial recent memory was tested in a Morris water maze delayed nonmatch-to-position task. In addition to memory, sensorimotor skills were also examined. Four- and 22-month-old rats were tested preoperatively, infused intraventricularly with recombinant human NGF or vehicle, and tested both during the 4 week infusion period and during the 4 weeks after discontinuation of the infusion. NGF significantly improved spatial recent memory in 22-month-old rats only, during the 4th week of infusion and for up to 4 weeks after discontinuation of the infusion. Although NGF did not affect overall sensorimotor skills during infusion in either age group, sensorimotor skills were significantly improved both 2 and 4 weeks after discontinuation of infusion in 22-month-old rats. These findings demonstrate that the beneficial effects of NGF on spatial recent memory can persist for up to 1 month after discontinuation of infusion and suggest that NGF can be used intermittently for the treatment of age-associated memory dysfunction and Alzheimer's disease.

In situ labeling of dying cortical neurons in normal aging and in Alzheimer's disease: correlations with senile plaques and disease progression.

We examined the degeneration of neocortical neurons in normal aging and Alzheimer's disease (AD) using terminal transferase (TdT)-mediated deoxyuridine triphosphate (d-UTP)-biotin nick-end labeling (TUNEL), a method that identifies DNA strand breaks and constitutes a positive marker for dying neurons. TUNEL was positive in neurons, glia, and microglial cells in AD but not in younger or age-matched cognitively characterized controls. Neuronal labeling in AD was most conspicuous in cortical layer III in the early stages of the disease and became more widespread as the disease progressed. In addition, we observed TUNEL of lamina III neurons in a subset of older subjects who had normal cognition but abundant neocortical senile plaques. In concert, the availability of a direct marker of dying neurons allows for specific correlations of cell death with other neuropathological markers as well as clinical variables. Observations from the present study suggest that the death of cortical neurons precedes the symptomatic stage of AD and evolves in parallel with the clinical progression of the disease and that there appears to be an association between the degree of cell death and the severity of senile plaques.

Axotomy as an experimental model of neuronal injury and cell death.

Axonal transection provides very useful paradigms to study cellular responses to injury, mechanisms of regeneration and plasticity, and processes that lead to nerve cell degeneration. Moreover, models of axotomy are valuable for testing experimental therapeutic approaches. Lesions can be made with great precision, and, depending on the neural system, location of the lesion, and age of the animal, these models allow the opportunity to examine a range of neuronal responses. Many parameters influence the character, evolution, and outcomes of axotomy-related processes. The most severe outcome of axotomy is cell death, very common in lesions of neurons of the central nervous system (CNS), although neurons of the peripheral nervous system (PNS) may also die if the transection is sufficiently close to the neuronal cell body or if lesions are performed in young animals. Studies of axotomy models have provided clues into the cellular/molecular events associated with neuronal death and the ways in which interventions can delay or prevent processes that lead to cell death. In this review, we select examples, primarily from our own work, to illustrate how axotomy models have enhanced our understanding of neuronal responses to injury, clarified mechanisms of both regeneration/plasticity and degeneration/ cell death, and allowed assessments of the utility of therapeutic approaches.

Ciliary neurotrophic factor stimulates the expression of glial fibrillary acidic protein by brain astrocytes in vivo.

Ciliary neurotrophic factor is a cytokine that has effects on neuronal survival and phenotype in vitro and in vivo. Ciliary neurotrophic factor has also been shown to have effects on microglia and oligodendrocytes in vitro and in vivo. In this study, we demonstrate in vivo effects of ciliary neurotrophic factor on astrocytes in both the injured and uninjured central nervous system. Ciliary neurotrophic factor increases the expression of glial fibrillary acidic protein and induces concomitant morphological changes in central nervous system astrocytes. Messenger RNA for both ciliary neurotrophic factor and the alpha-component of the ciliary neurotrophic factor receptor is demonstrated in the optic nerve, an essentially pure population of central nervous system glia. We also report here that the promoter region of the glial fibrillary acidic protein gene contains sequences thought to confer direct ciliary neurotrophic factor modulation of glial fibrillary acidic protein gene transcription. Although it is thought that astrocytes are a source of endogenous ciliary neurotrophic factor in the central nervous system and that neurons express the alpha-component of the ciliary neurotrophic factor receptor, the results of the present investigation suggest that astrocytes themselves respond to ciliary neurotrophic factor and that ciliary neurotrophic factor may also be important in glial cell-cell interactions.

Selective effects of nerve growth factor on spatial recent memory as assessed by a delayed nonmatching-to-position task in the water maze.

Nerve growth factor (NGF) ameliorates age-related deficits in certain types of memory in rats. Although the effects of NGF on reference memory are well documented, the influence of NGF on recent memory is less well understood. The issue of recent memory is of primary importance in the design of therapies for cognitive disorders, because this type of memory is impaired in elderly humans and is severely affected early in the course of Alzheimer's disease (AD). The present study was designed to evaluate the efforts of NGF on recent memory in a task that used escape from water as the motivating stimulus and used the same design as forced-choice recognition tasks given to humans. Fischer-344 rats, 4 months old (4MO) or 23 months old (23MO), were pretested in a new spatial recent memory task designed for the Morris water maze, a delayed nonmatching-to-position task, and infused intraventricularly with recombinant human NGF or vehicle. After 2 weeks of NGF infusion, no substantial changes in behavior were observed in either age group. However, NGF treatment extended over 4 weeks improved considerably the choice accuracy of 23MO rats to a level similar to the performance of 4MO rats. These results, together with our previous work (Markowska et al., 1994), indicate that the effects of NGF on spatial recent memory are more intense than on spatial reference memory. NGF suppressed the body weight gain in 4MO rats but did not affect 23MO rats. In 23MO rats, NGF mildly counteracted age-related deficits in inhibitory avoidance, but did not have an effect in young rats.

Motor neuron disease and model systems: aetiologies, mechanisms and therapies.

The phenotypes of many neurological diseases, including motor neuron disease (amyotrophic lateral sclerosis; ALS) and Alzheimer's disease (AD), are determined by the vulnerabilities of populations of nerve cells and the character/ evolution of cellular abnormalities. Because different cell types respond selectively to individual trophic factors, these factors may be useful in ameliorating pathology in cells that express their cognate receptors. To test therapies for ALS and AD, investigators require model systems. Although there are a variety of models of ALS, two models are particularly attractive: transgenic mice that express human superoxide dismutase 1 (SOD-1) mutations linked to familial ALS develop paralysis associated with a gain of adverse property of the mutant SOD; and axotomy of facial axons in neonatal rats, a manipulation that causes retrograde cell degeneration, which can be ameliorated by several trophic factors.