Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. Neuronal degeneration is accompanied by primarily oligodendrocytic accumulation of ␣-synuclein (␣syn) as opposed to the neuronal inclusions more commonly found in other ␣-synucleinopathies such as Parkinson's disease. It is unclear how ␣syn accumulation in oligodendrocytes may lead to the extensive neurodegeneration observed in MSA; we hypothesize that the altered expression of oligodendrocyte-derived neurotrophic factors by ␣syn may be involved. In this context, the expression of a number neurotrophic factors reportedly expressed by oligodendrocytes [glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor 1 (IGF-1), as well as basic fibroblast growth factor 2 (bFGF2), reportedly astrocyte derived] were examined in transgenic mouse models expressing human ␣syn (h␣syn) under the control of either neuronal (PDGF␤ or mThy1) or oligodendrocytic (MBP) promoters. Although protein levels of BDNF and IGF-1 were altered in all the ␣syn transgenic mice regardless of promoter type, a specific decrease in GDNF protein expression was observed in the MBP-h␣syn transgenic mice. Intracerebroventricular infusion of GDNF improved behavioral deficits and ameliorated neurodegenerative pathology in the MBP-h␣syn transgenic mice. Consistent with the studies in the MBP-h␣syn transgenic mice, analysis of GDNF expression levels in human MSA samples demonstrated a decrease in the white frontal cortex and to a lesser degree in the cerebellum compared with controls. These results suggest a mechanism in which ␣syn expression in oligodendrocytes impacts on the trophic support provided by these cells for neurons, perhaps contributing to neurodegeneration.

This human study is based on an established cohort of "SuperAgers," 80ϩ-year-old individuals with episodic memory function at a level equal to, or better than, individuals 20 -30 years younger. A preliminary investigation using structural brain imaging revealed a region of anterior cingulate cortex that was thicker in SuperAgers compared with healthy 50-to 65-year-olds. Here, we investigated the in vivo structural features of cingulate cortex in a larger sample of SuperAgers and conducted a histologic analysis of this region in postmortem specimens. A region-of-interest MRI structural analysis found cingulate cortex to be thinner in cognitively average 80ϩ year olds (n ϭ 21) than in the healthy middle-aged group (n ϭ 18). A region of the anterior cingulate cortex in the right hemisphere displayed greater thickness in SuperAgers (n ϭ 31) compared with cognitively average 80ϩ year olds and also to the much younger healthy 50 -60 year olds (p Ͻ 0.01). Postmortem investigations were conducted in the cingulate cortex in five SuperAgers, five cognitively average elderly individuals, and five individuals with amnestic mild cognitive impairment. Compared with other subject groups, SuperAgers showed a lower frequency of Alzheimer-type neurofibrillary tangles (p Ͻ 0.05). There were no differences in total neuronal size or count between subject groups. Interestingly, relative to total neuronal packing density, there was a higher density of von Economo neurons (p Ͻ 0.05), particularly in anterior cingulate regions of SuperAgers. These findings suggest that reduced vulnerability to the age-related emergence of Alzheimer pathology and higher von Economo neuron density in anterior cingulate cortex may represent biological correlates of high memory capacity in advanced old age.

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Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4–8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing.