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An early hallmark of neuronal degeneration is distal transport loss and axon pathology. Glaucoma involves the degeneration of retinal ganglion cell (RGC) neurons and their axons in the optic nerve. Here we show that, like other neurodegenerations, distal axon injury appears early in mouse glaucoma. Where RGC axons terminate in the superior colliculus, reduction of active transport follows a retinotopic pattern resembling glaucomatous vision loss. Like glaucoma, susceptibility to transport deficits increases with age and is not necessarily associated with elevated ocular pressure. Transport deficits progress distal-to-proximal, appearing in the colliculus first followed by more proximal secondary targets and then the optic tract. Transport persists through the optic nerve head before finally failing in the retina. Although axon degeneration also progresses distal-to-proximal, myelinated RGC axons and their presynaptic terminals persist in the colliculus well after transport fails. Thus, distal transport loss is predegenerative and may represent a therapeutic target. axon transport | optic neuropathy | retinal ganglion cell | glaucoma | optic nerve doi: 10.1073/pnas.0913141107

The preoccupation for improving the quality of life, for persons with different handicaps, led to extended research in the area of functional stimulation. Due to its advantages compared to electrical stimulation, magnetic stimulation of the human nervous system is now a common technique in modern medicine. A difficulty of this technique is the need for accurate focal stimulation. Another one is the low efficiency of power transfer from the coil to the tissue. To address these difficulties, coils with special geometries must be designed. Index Terms--Coil design, energetic efficiency, magnetic stimulation, nervous system.

Background Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood. Methods and Findings A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures. Conclusions The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny., Introduction In recent decades there has been increased attention to health outcomes in the offspring of older fathers. Evidence shows that advanced paternal age (APA) is associated with an increased [...]

The glutamate receptor was one of the most intensely investigated targets for neuroprotection. However, numerous clinical trials of glutamate receptor antagonists for the treatment of stroke were unsuccessful. These failures have led to pessimism in the field. But recent advances could provide hope for the future. This minireview looks beyond the traditional mechanism of glutamate-receptor-driven excitotoxicity to identify other mechanisms of ionic imbalance. These advances include findings implicating sodium-calcium exchangers, hemi-channels, volume-regulated anion channels, acid-sensing channels, transient receptor potential channels, nonselective cation channels and signaling cascades that mediate crosstalk between redundant pathways of cell death. Further in vivo validation of these pathways could ultimately lead us to new therapeutic targets for stroke, trauma and neurodegeneration.

The impact of the prion protein (PrP) on the ubiquitin-proteasome pathway in animals, including cows is studied. These proteins are found to highly interfere in the proteasomal activity of the animals, leading to prion diseases and madness in cows.

Treatment with either estradiol or an estrogen receptor (ER)[alpha] ligand has been shown to be both antiinflammatory and neuroprotective in a variety of neurological disease models, but whether neuroprotective effects could be observed in the absence of an antiinflammatory effect has remained unknown. Here, we have contrasted effects of treatment with an ER[alpha] vs. an ER[beta] ligand in experimental autoimmune encephalomyelitis, the multiple sclerosis model with a known pathogenic role for both inflammation and neurodegeneration. Clinically, ER[alpha] ligand treatment abrogated disease at the onset and throughout the disease course. In contrast, ER[beta] ligand treatment had no effect at disease onset but promoted recovery during the chronic phase of the disease. ER[alpha] ligand treatment was antiinflammatory in the systemic immune system, whereas ER[beta] ligand treatment was not. Also, ER[alpha] ligand treatment reduced CNS inflammation, whereas ER[beta] ligand treatment did not. Interestingly, treatment with either the ER[alpha] or the ER[beta] ligand was neuroprotective, as evidenced by reduced demyelination and preservation of axon numbers in white matter, as well as decreased neuronal abnormalities in gray matter. Thus, by using the ER[beta] selective ligand, we have dissociated the antiinflammatory effect from the neuroprotective effect of estrogen treatment and have shown that neuroprotective effects of estrogen treatment do not necessarily depend on antiinflammatory properties. Together, these findings suggest that ER[beta] ligand treatment should be explored as a potential neuroprotective strategy in multiple sclerosis and other neurodegenerative diseases, particularly because estrogen-related toxicities such as breast and uterine cancer are mediated through ER[alpha]. experimental autoimmune encephalomyelitis | neuroprotection | multiple sclerosis selective estrogen receptor modulators

The classical divide between degenerative and inflammatory disorders of the CNS is vanishing as accumulating evidence shows that inflammatory processes are important in the pathophysiology of primarily degenerative disorders, and neurodegeneration complicates primarily inflammatory diseases of the brain and spinal cord. Here, we review the contribution of degenerative and inflammatory processes to CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and HIV-associated dementia. An early combination of neuroprotective and anti-inflammatory approaches to these disorders seems particularly desirable because isolated treatment of one pathological process might worsen another. We also discuss the apparently unique opportunity to modify neurodegeneration and neuroinflammation simultaneously by pharmacological manipulation of the endocannabinoid system in the CNS and in peripheral immune cells. Current knowledge of this system and its involvement in the above CNS disorders are also reviewed.

The main goal of this work is the generation of ground-truth data for the validation of atrophy measurement techniques, commonly used in the study of neurodegenerative diseases such as dementia. Several techniques have been used to measure atrophy in cross-sectional and longitudinal studies, but it is extremely difficult to compare their performance since they have been applied to different patient populations. Furthermore, assessment of performance based on phantom measurements or simple scaled images overestimates these techniques' ability to capture the complexity of neurodegeneration of the human brain. We propose a method for atrophy simulation in structural magnetic resonance (MR) images based on finite-element methods. The method produces cohorts of brain images with known change that is physically and clinically plausible, providing data for objective evaluation of atrophy measurement techniques. Atrophy is simulated in different tissue compartments or in different neuroanatomical structures with a phenomenological model. This model of diffuse global and regional atrophy is based on volumetric measurements such as the brain or the hippocampus, from patients with known disease and guided by clinical knowledge of the relative pathological involvement of regions and tissues. The consequent biomechanical readjustment of structures is modelled using conventional physics-based techniques based on biomechanical tissue properties and simulating plausible tissue deformations with finite-element methods. A thermoelastic model of tissue deformation is employed, controlling the rate of progression of atrophy by means of a set of thermal coefficients, each one corresponding to a different type of tissue. Tissue characterization is performed by means of the meshing of a labelled brain atlas, creating a reference volumetric mesh that will be introduced to a finite-element solver to create the simulated deformations. Preliminary work on the simulation of acquisition artefacts is also presented. Cross-sectional and longitudinal sets of simulated data are shown and a visual classification protocol has been used by experts to rate real and simulated scans according to their degree of atrophy. Results confirm the potential of the proposed methodology. Index Terms--Alzheimer's disease, atlas, atrophy simulation, creation of validation image databases, dementia, design of ground truth, finite-element methods, magnetic resonance imaging, mesh warping, modelling, validation.

The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1-/-; En2-/-). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1+/-;En2-/-), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder. dopamine | midbrain | mouse mutant | neurodegenerative disease | substantia nigra

Purpose: The aim of this pilot feasibility study was to evaluate the effects of an innovative, Internet-based psychosocial intervention for family caregivers of older adults with neurodegenerative disease. Design and Methods: After receiving signed informed consent from each participant, we randomly assigned 66 caregivers to an Internet-based intervention or to a no-intervention control group. The intervention group received computers and training in order to access a password-protected Web site with links to information, e-mail, and threaded discussion. Unique to the Web site was a video-conferencing link that supported caregivers' participation in a 10-session, manual-guided psychosocial support group, followed by 12 additional online sessions facilitated by a group member. Participants completed health-status and stress-response measures at baseline and 6-month follow-up. Results: Content analysis of archived video sessions showed (a) reliable adherence to the manual-guided support-group intervention and (b) online group discussion themes similar to those in face-to-face caregiver support groups. Analyses of stress-response outcome data showed significant between-group differences, with the intervention group experiencing a decline in stress compared with an escalation in stress for the control group. Implications: Despite the limitations of this pilot study in terms of limited sample size and 54% dropout of control participants at 6-month follow-up, the results provide preliminary supportive evidence for a technology-based psychosocial intervention for family caregivers of individuals with neurodegenerative disease. Key Words: Virtual psychosocial support groups, Caregivers, Neurodegenerative disease, Web-based intervention, Technology

OBJECTIVES. Newborns delivered before 28 weeks' gestation commonly have white matter lesions on MRI that are associated with adverse neurodevelopmental outcomes. Our objective was to determine the risk factors for MRI-detectable white matter injury in infants delivered before 28 weeks' gestation who were treated with prophylactic indomethacin. METHODS. This was a prospective cohort study conducted at the intensive care nursery at University of California San Francisco Children's Hospital. Patients included 57 premature newborns between 24 and 27 (+6 days) weeks' gestation at birth (October 1998 to October 2004). We identified perinatal and neonatal risk factors associated with moderate-severe "white matter injuries" (T1 signal abnormalities >2 mm or >3 areas of T1 abnormality) and moderate-severe "brain abnormality" (moderate-severe white matter injuries, any degree of ventriculomegaly, or severe intraventricular hemorrhage) on MRI. Infants were studied with MRI at 31.1 weeks' postmenstrual age (median). RESULTS. Moderate-severe white matter injuries were detected in 12 (21%) of 53 preterm newborns, and 20 (35%) of 57 had moderate-severe brain abnormality. Prolonged indomethacin exposure was the only risk factor independently associated with a lower risk of white matter injury or brain abnormality, even when adjusting for the presence of a hemodynamically significant PDA, gestational age at birth, prenatal betamethasone, systemic infection, and days of mechanical ventilation. CONCLUSIONS. In this observational study, a longer duration of indomethacin exposure was associated with less white matter injury in infants delivered before 28 weeks' gestation. A randomized trial of prolonged indomethacin treatment is needed to determine whether indomethacin can decrease white matter injury and neurodevelopmental abnormalities. Key Words periventricular leukomalacia, MRI, brain injury, patent ductus arteriosus, indomethacin, Abbreviations IVH--intraventricular hemorrhage PMA--postmenstrual age PDA--patent ductus arteriosus CI--confidence interval OR--odds ratio NEURODEVELOPMENTAL ABNORMALITIES ARE common after premature birth. (1) These motor and cognitive deficits are not necessarily associated with [...]

Recombinant human nerve growth factor (rhNGF) is regarded as the most promising therapy for neurodegeneration of the central and peripheral nervous systems as well as for several other pathological conditions involving the immune system. However, rhNGF is not commercially available as a drug. In this work, we provide data about the production on a laboratory scale of large amounts of a rhNGF that was shown to possess in vivo biochemical, morphological, and pharmacological effects that are comparable with the murine NGF (mNGF), with no apparent side effects, such as allodynia. Our rhNGF was produced by using conventional recombinant DNA technologies combined with a biotechnological approach for high-density culture of mammalian cells, which yielded a production of [approximately equal to]21.5 [+ or -] 2.9 mg/liter recombinant protein. The rhNGF-producing cells were thoroughly characterized, and the purified rhNGF was shown to possess a specific activity comparable with that of the 2.5S mNGF by means of biochemical, immunological, and morphological in vitro studies. This work describes the production on a laboratory scale of high levels of a rhNGF with in vitro and, more important, in vivo biological activity equivalent to the native murine protein. mammalian cells | miniPerm system | neurotrophic activity

ABBREVIATION. PVL, periventricular leukomalacia. The dominant encephalopathy of premature infants is considered generally to involve principally white matter. (1) Periventricular leukomalacia (PVL) is the major form of white matter injury [...]

Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy caused by recessive mutations in either a gene encoding a dual-specificity phosphatase, known as laforin, or a recently identified gene encoding the protein known as malin. Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. Missense mutations in malin that are present in LD patients abolish its ability to polyubiquitinate and signal the degradation of laforin. Our results demonstrate that laforin is a physiologic substrate of malin, and we propose possible models to explain how recessive mutations in either malin or laforin result in LD. Furthermore, these data distinguish malin as an E3 Ub ligase whose activity is necessary to prevent a neurodegenerative disease that involves formation of nonproteinacious inclusion bodies. progressive myoclonus epilepsy | phosphatase | neurodegenerative disease

Nerve growth factor (NGF) delivery to the brain of patients appears to be an emerging potential therapeutic approach to neurodegenerative disease, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracerebroventricular infusion and gene therapy. We previously showed that intranasal administration of NGF determined an amelioration of cholinergic deficit and a decrease in the number of phosphotau-positive neurons and of [beta]-amyloid accumulation in AD11 mice, which express transgenic antibodies neutralizing NGF action and exhibit a progressive Alzheimer-like neurodegeneration. In this study, we report that the Alzheimer-like neurodegeneration in AD11 mice is linked to progressive behavioral deficits in visual recognition memory and spatial memory starting from 4 months of age. To establish whether intranasal administration of NGF, started after the appearance of the first memory deficits, could revert the cognitive deficits in AD11 mice, we assessed the performance of NGF-treated or control AD11 mice in the object recognition test and in a test of memory for place and context. Deficits exhibited by untreated AD11 mice could be rescued by the intranasal administration of NGF. Thus, this route of administration provides a promising way to deliver NGF to the brain in a therapeutic perspective. Alzheimer's disease | behavior | mouse model

The Bcl-2 family of apoptotic-regulating proteins plays important roles during both neural development and maintenance of tissue homeostasis. The major antiapoptotic family members, Bcl-[x.sub.L] and Bcl-2, and the major proapoptotic [...]

Individuals with neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease are benefiting from drugs developed to act on a single molecular target. However, current pharmacological approaches are limited in their ability to modify significantly the course of the disease, and offer incomplete and transient benefit to patients. New therapeutic strategies comprise drug candidates designed specifically to act on multiple neural and biochemical targets for the treatment of cognition impairment, motor dysfunction, depression and neurodegeneration. Examples include the development of single molecular entities that combine two or more of the following properties: (i) cholinesterase inhibition; (ii) activation or inhibition of specific subtypes of acetylcholine receptors or [alpha]-adrenoceptors; (iii) anti-inflammatory activity; (iv) monoamine oxidase inhibition; (v) catechoI-O-methyl transferase inhibition; (vi) nitric oxide production; (vii) neuroprotection; (viii) anti-apoptotic activity; and (ix) activation of mitochondrial-dependent cell-survival genes and proteins. These bi- or multi-functional compounds might provide greater symptomatic efficacy, and better utility as potential neuroprotective disease-modifying drugs.

Progress toward elucidating the function of [alpha][sub.1B]-adrenergic receptors ([alpha][sub.1B]ARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate [alpha][sub.1B]-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active [alpha][sub.1B]ARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in [alpha][sub.1B]-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the [alpha][sub.1]AR antagonist terazosin, indicating that [alpha][sub.1]AR signaling participated directly in the pathology. Our results indicate that overstimulation of [alpha][sub.1B]AR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown., Author(s): Michael J. Zuscik [1]; Scott Sands [2]; Sean A. Ross [1]; David J. J. Waugh [1]; Robert J. Gaivin [1]; David Morilak [2]; Dianne M. Perez (corresponding author) [1] [...]

On May 9, less than a month before her husband's death, former First Lady Nancy Reagan spoke at the Juvenile Diabetes Research Foundation gala in Los Angeles. That night she [...]

Neuroinflammation, characterized by activated microglia and infiltrating T cells, is a prominent pathological feature in neurodegenerative diseases. However, whether this inflammation contributes to neuronal injury or is a late consequence of neuronal injury is unclear. In this issue of the JCI, Brochard et al. report that [CD4.sup.+] T cells are cytotoxic in a mouse model of Parkinson disease (PD) (see the related article beginning on page 182). Specifically, invading T lymphocytes contributed to neuronal cell death via the Fas/FasL pathway. The results implicate the adaptive immune system in the pathogenesis of Parkinson neurodegeneration and provide a meaningful rationale for immune-based therapies for PD., Neuroinflammation in Parkinson disease Parkinson disease (PD) is a motor system disorder, which is characterized by tremor, rigidity, slowed movements, and impaired balance and coordination and results from the loss [...]

Although monoamine oxidase (MAO) inhibitors are not used as extensively as other antidepressants, they continue to have an important place in the armamentarium of drugs used to treat psychiatric and [...]

The development and advantages of several safer active and passive immunotherapeutic approaches for the treatment of the neurodegenerative diseases in humans are discussed. The direct antibody-mediated disruption of aggregates and the neutralization of toxic soluble proteins are shown to be few of the mechanisms that play a significant role in these therapies.

Recent articles have highlighted numerous additional functions of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) that are independent of its well-documented glycolytic function. One of the most intriguing of these functions is as an [...]