Cerebral Palsy

During the last decade much important new information relating to the metabolic pathway from methionine to homocysteine has been gained. Interest has been stimulated by the discovery of two novel disorders, glycine N-methyltransferase deficiency and S-adenosylhomocysteine hydrolase deficiency. Another disorder in this pathway, methionine adenosyltransferase deficiency, has been increasingly detected, thanks to the expansion of newborn screening programmes by tandem mass spectrometry technology. These significant steps allow important insight into the pathogenesis of these three disorders, as well as into the mechanisms of damage to various organs (liver, brain, muscle) and point to the relevance of these disorders for crucial biological processes such as methylation, transsulfuration or carcinogenesis in mammals, the pathogenesis of numerous pathological conditions, in particular those associated with hyperhomocysteinaemia, the action and possible toxicity of some drugs or consequences of nutritional variations. This review summarizes current knowledge of three inherited disorders in this metabolic pathway and draws attention to their much broader significance for human health and understanding of important biological processes.

There is increasing evidence of oxidative stress in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Because mitochondrial DNA (mtDNA) is susceptible to oxidative damage, somatic mtDNA mutations may be induced by oxidative stress. Most of the studies examining mitochondrial mutations have been performed on postmortem brain tissues of AD patients. This study examined peripheral blood samples of AD and MCI patients to determine if peripheral mtDNA mutations are associated with these two conditions. A total of 236 subjects, including 71 AD patients, 84 amnestic MCI patients, 41 cognitively normal aging controls, and 40 young controls, were recruited. There was heteroplasmy of the mtDNA D310 polycytosine repeat region in 37 of 71 (52.1%) AD patients and this was significantly more frequent than in MCI patients (31.0%), normal aging (31.7%), and young controls (27.5%). However, subjects with amnestic MCI did not have a significantly higher rate of heteroplasmy in D310 than cognitively normal elderly subjects. The heteroplasmic alterations of D310 were more frequently in subjects with a larger number of polycytosine repetitions. Insertion of cytosine was the most common mutation type. The results suggest that mutations of mtDNA 310 region are frequently present in the peripheral blood of AD patients. Further prospective investigations to determine if MCI subjects with D310 mutations develop AD is warranted.

A role for innate immunity in neurodegenerative diseases is now widely accepted, although debate continues over the relative contributions of these processes to disease progression and/or to disease amelioration. The idea that microglia and cytokines are important in neurodegeneration arose from neuropathological observations, especially in Alzheimer’s disease. Microglia are invariant components of the Abeta plaques of Alzheimer’s disease, where they show a waxing and waning of numbers, activation state, and cytokine expression during plaque progression. This is in contrast to diffuse Abeta deposits sometimes found in abundance in the brain of non-demented elderly individuals, which do not contain activated microglia. In Alzheimer’s disease, plaque-associated astrocytes, which also produce paracrine mediators, show a pattern similar to that of microglia; and the associated plaque progression is accompanied by progressive damage to and loss of adjacent neurons. Further, activated microglia and astrocytes show a progressive pattern of association with neurofibrillary tangles. These observations, together with known functions of the involved cytokines, originally suggested a central role for immunological phenomena in driving disease progression in Alzheimer’s disease. Further observations have extended these ideas to alpha-synuclein-based diseases (Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy) as well as other neurodegenerative diseases and conditions.

Implicit memory for emotional facial expressions (EFEs) was investigated in young adults, healthy old adults, and mild Alzheimer’s disease (AD) patients. Implicit memory is revealed by the effect of experience on performance by studying previously encoded versus novel stimuli, a phenomenon referred to as perceptual priming. The aim was to assess the changes in the patterns of priming as a function of aging and dementia. Participants identified EFEs taken from the Facial Action Coding System and the stimuli used represented the emotions of happiness, sadness, surprise, fear, anger, and disgust. In the study phase, participants rated the pleasantness of 36 faces using a Likert-type scale. Subsequently, the response to the 36 previously studied and 36 novel EFEs was tested when they were randomly presented in a cued naming task. The results showed that implicit memory for EFEs is preserved in AD and aging, and no specific age-related effects on implicit memory for EFEs were observed. However, different priming patterns were evident in AD patients that may reflect pathological brain damage and the effect of stimulus complexity. These findings provide evidence of how progressive neuropathological changes in the temporal and frontal areas may affect emotional processing in more advanced stages of the disease.

As neurotrophic factors play an important role in development and maintenance of global central nervous system (CNS) function, we supposed that glial cell-line derived neurotrophic factor (GDNF), which has been extensively studied for its survival promoting effects especially concerning catecholaminergic neurons, also plays a significant role in neurodegenerative disease characterized mainly by damage of cholinergic CNS neurons like AD. Here we compared GDNF concentrations in serum and cerebrospinal fluid (CSF) of patients with probable Alzheimer’s disease (AD) and normal controls (NC). While GDNF concentrations in CSF were significantly increased in patients with AD (291.7 +/- 85.8 pg/ml) compared with NC subjects (218.7 +/- 93.3 pg/ml, p = 0.012), GDNF concentration of AD patients (486.5 +/- 72.3 pg/ml) in serum were significantly decreased compared with the NC group (711.5 +/- 186.5 pg/ml, p < 0.001). Increased GDNF in CSF of AD might be due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease and/or impairment of CSF turnover. Decreased serum concentration of GDNF might be related to altered function of the blood brain barrier thus disturbing clearance or facilitating passover of potentially harmful metabolites.

Edaravone is a novel free radical scavenger that is clinically employed in patients with acute cerebral infarction, but has not previously been used to treat traumatic brain injury (TBI). In this study, we investigated the effect of edaravone administration on rat TBI. In particular, we used immunohistochemistry to monitor neural stem cell (NSC) proliferation around the area damaged by TBI. Two separate groups of rats were administered saline or edaravone (3 mg/kg) after TBI and then killed chronologically. We also used ex vivo techniques to isolate NSCs from the damaged region and observed nestin-positive cells at 1, 3, and 7 days following TBI in both saline- and edaravone-treated groups. At 3 days following TBI in both groups, there were many large cells that morphologically resembled astrocytes. At 1 and 7 days following TBI in the saline group, there were a few small nestin-positive cells. However, in the edaravone group, there were many large nestin-positive cells at 7 days following TBI. At 3 and 7 days following TBI, the number of nestin-positive cells in the edaravone group increased significantly compared with the saline group. There were many single-stranded DNA-, 8-hydroxy-2′-deoxyguanosine-, and 4-hydroxy-2-nonenal-positive cells in the saline group following TBI, but only a few such cells in the edaravone group following TBI. Furthermore, almost all ssDNA-positive cells in the saline group co-localized with Hu, nestin, and glial fibrillary acidic protein (GFAP) staining, but not in the edaravone group. In the ex vivo study, spheres could only be isolated from injured brain tissue in the saline group at 3 days following TBI. However, in the edaravone group, spheres could be isolated from injured brain tissue at both 3 and 7 days following TBI. The number of spheres isolated from injured brain tissue in the edaravone group showed a significant increase compared with the saline group. The spheres isolated from both saline and edaravone groups were immunopositive for nestin, but not Tuj1 or vimentin. Moreover, the spheres differentiated into Tuj1-, GFAP-, and O4-positive cells after 4 days in culture without bFGF. This result indicated that the spheres were neurospheres composed of NSCs that could differentiate into neurons and glia. Edaravone administration inhibited production of free radicals known to induce neuronal degeneration and cell death after brain injury, and protected nestin-positive cells, including NSCs, with the potential to differentiate into neurons and glia around the area damaged by TBI.

Heavy alcohol exposure produces profound damage to the developing central nervous system (CNS) as well as the adult brain. Children with fetal alcohol spectrum disorders (FASD) have a variety of cognitive, behavioral, and neurological impairments. FASD currently represents the leading cause of mental retardation. Excessive alcohol consumption is associated with Wernicke-Korsakoff syndrome (WKS) and neurodegeneration in the adult brain. Although the cellular/molecular mechanism underlying ethanol’s neurotoxicity has not been fully understood, it is generally believed that oxidative stress plays an important role. Identification of neuroprotective agents that can ameliorate ethanol neurotoxicity is an important step for developing preventive/therapeutic strategies. Targeting ethanol-induced oxidative stress using natural antioxidants is an attractive approach. Anthocyanins, a large subgroup of flavonoids present in many vegetables and fruits, are safe and potent antioxidants. They exhibit diverse potential health benefits including cardioprotection, anti-atherosclerotic activity, anti-cancer, anti-diabetic, and anti-inflammation properties. Anthocyanins can cross the blood-brain barrier and distribute in the CNS. Recent studies indicate that anthocyanins represent novel neuroprotective agents and may be beneficial in ameliorating ethanol neurotoxicity. In this review, we discuss the evidence and potential of anthocyanins in alleviating ethanol-induced damage to the CNS. Furthermore, we discuss possible underlying mechanisms as well as future research approaches necessary to establish the therapeutic role of anthocyanins.

BACKGROUND: Lead is known to be a health hazard to the human brain and nervous system based on data from epidemiologic studies. However, few studies have examined the mechanism or biochemical changes caused by lead in the human brain, although recently some have used magnetic resonance spectroscopy (MRS) to test brain metabolism in vivo. OBJECTIVES: In this study, we used 3-T MRS to investigate brain metabolism in workers chronically exposed to lead and matched nonexposed controls. MATERIALS : METHODS: Twenty-two workers at a lead paint factory served as chronically exposed subjects of this study. These workers did not have any clinical syndromes. Eighteen age- and sex-matched nonexposed healthy volunteers served as controls. We measured blood and bone lead and used a 3-T MRS to measure their levels of brain N-acetyl aspartate (NAA), choline (Cho), and total creatine (tCr). A structural questionnaire was used to collect demographic, work, and health histories and information about their life habits. RESULTS: All the MRS measures were lower in the lead-exposed group. Increased blood and bone lead levels correlated with declines in Cho:tCr ratios, especially in the occipital lobe, where changes in all gray, subcortical, and white matter were significant. Increases in blood and patella lead in every layer of the frontal lobe correlated with significant decreases in NAA:tCr ratios. One of the strongest regression coefficients was -0.023 (SE = 0.005, p < 0.001), which was found in the NAA:tCr ratio of frontal gray matter. DISCUSSION: We conclude that chronic exposure to lead might upset brain metabolism, especially NAA:tCr and Cho:tCr ratios. Brain NAA and Cho are negatively correlated to blood and bone lead levels, suggesting that lead induces neuronal and axonal damage or loss. The most significant changes occurred in frontal and occipital lobes, areas in which previous neurobehavioral studies have shown memory and visual performance to be adversely affected by lead toxicity.

BACKGROUND: Many factors may predict mortality and disability after traumatic brain injury (TBI), including age and injury severity. However, the role of raceethnicity has typically been studied tangentially or in homogeneous settings. We investigated whether raceethnicity was associated with medical outcomes at a single, diverse center. METHODS: We retrospectively identified patients with TBI older than 17 years with blunt injuries admitted to a Level I trauma center from 2001 to 2004. Glasgow Outcome Scale (GOS) was used to determine outcome at discharge. We performed multivariable logistic regression on two measures of outcome by dichotomizing Glasgow Outcome Scale scores. RESULTS: We identified 357 patients with TBI from five categories: whites (46.2%), Asians (19.9%), Hispanics (17.9%), blacks (10.9%), and otherunknown (5.0%). Without adjusting for other factors, Asians experienced higher mortality (odds ratio [OR] = 2.25, p = 0.01) compared with whites but not degree of disability. After adjusting for age and Injury Severity Score, a weaker trend remained for higher mortality in Asians (OR = 1.38, p = 0.35), and after excluding cases of assault, the finding was again significant (OR = 2.00, p = 0.04). We also confirmed the recently reported OR of higher mortality among blacks (OR = 1.30). Hispanics seemed to do slightly better at discharge. CONCLUSIONS: The question of whether and how race plays a role in TBI is controversial. At a single, diverse center, we found that mortality is associated with race, age, and Injury Severity Score. Future clinical studies will benefit from detailed genotypic and phenotypic data and should balance larger sample sizes with ethnic diversity.

Purpose: To determine the relationship of the photopic negative response (PhNR) of the photopic electroretinogram (ERG) with the degree of circulatory disturbances in eyes following central retinal artery occlusion (CRAO). Methods: The circulatory disturbance was graded as mild (group 1) when the arm-to-retina transmission time was <30 s, moderate (group 2) when the time was >30 s and severe (group 3) when concurrent choroidal circulatory damage was found. For statistical analysis, groups 1, 2 and 3 were scored as 1, 2 and 3, respectively. Photopic ERGs were elicited by either short-flash (SF) or long-flash (LF) stimuli. Results: Both the SF and LF PhNR were significantly reduced in groups 2 and 3. The PhNR amplitude was negatively correlated with the severity of the ocular circulatory disturbances (p = 0.0498, rho = -0.507 for SF PhNR; p = 0.0050, rho = -0.750 for LF PhNR). Conclusion: The amplitude of the PhNR became more reduced as the severity of the circulatory disturbances increased in eyes with CRAO. Copyright © 2009 S. Karger AG, Basel.