氧化应激与MS

Neurodegeneration in multiple sclerosis: The role of oxidative stress and excitotoxicity

R.E. Gonsette, a,

aNational Centre for Multiple Sclerosis, B 1820 Melsbroek, Belgium


Received 19 February 2008; accepted 27 June 2008. Available online 5 August 2008.

Abstract
In multiple sclerosis (MS) disability results from neuronal and axonal loss, the hallmark of neurodegenerative diseases (ND). Neurodegeneration is initiated by microglia activation and mediated by oxidative stress and excitotoxicity. The same sequence of events has been consistently observed in MS. However, microglia activation correlates with a marked cell infiltration in MS but not in ND. In both pathological states, peroxynitrite is the common initiating factor of oxidative stress and excitotoxicity and is thus a potential interesting therapeutic target. Oxidative stress leads to multiple lipid and protein damages via peroxidation and nitration processes. The pathomechanisms of excitotoxicity are complex involving glutamate overload, ionic channel dysfunction, calcium overload, mitochondriopathy, proteolytic enzyme production and activation of apoptotic pathways. The inflammatory component in MS is important for the design of therapeutic strategies. Inflammation not only causes axonal and neuronal loss but it also initiates the degenerative cascade in the early stage of MS. Potent anti-inflammatory agents are now available and it is not unreasonable to think that an early blockade of inflammatory processes might also block associated degenerative mechanisms and delay disability progression. The development of neuroprotective drugs is more problematic. Indeed, given the multiple and parallel mechanisms involved in neurodegeneration, modulation of a single specific pathway will likely yield a partial benefit if any.

Keywords: Multiple sclerosis; Oxidative stress; Excitotoxicity; Peroxynitrite; Microglia; Uric acid

Article Outline
1. Introduction
2. Oxidative stress
3. Excitotoxicity
4. Discussion
5. Conclusion
References

1. Introduction
Multiple sclerosis (MS) has long been considered as an immune-mediated inflammatory disease characterized by re-activation of antigen-specific cells, microglial activation, recruitment of systemic immunocompetent cells and production of cytotoxic mediators leading to neural tissue damage (inflammatory cascade). It was generally believed that demyelination caused by inflammatory processes was responsible not only for acute neurological deficits but also for disability progression.

An accumulating body of evidence has challenged this earlier concept and demonstrates that disability results from neuronal and axonal loss rather than from demyelination. Pathomechanisms of neurodegeneration have been extensively investigated in neurodegenerative diseases (ND) and are basically mediated by oxidative stress and excitotoxicity (degenerative cascade).

Pathological and clinical data collected in the past decade revealed that inflammation abates over time suggesting that MS pathomechanisms vary according to the stage of the disease. Recently the concept of MS as a biphasic disease divided into an inflammatory relapsing-remitting (RR) phase and a degenerative secondary-progressive (SP) phase has thus emerged. It appears evident however that the differences concerning the pathomechanisms involved in the successive phases of MS are quantitative rather than qualitative. Indeed, microglial activation predominates in the RR phase and is sustained in the RP phases. Cellular immunity predominates during the RR phase and clearly abates in the SP phase. Humoral immunity, oxidative stress and excitotoxicity prevail during the SP phase. Importantly, the inflammatory and degenerative cascades are closely interactive. The purpose of this review is to situate oxidative stress and excitotoxicity among the multiple pathological mechanisms involved in MS.

2. Oxidative stress
Oxygen is essential for aerobic life but its metabolisms lead to the formation of harmful radical oxygen species (ROS). During species evolution, protective mechanisms against oxygen radicals have been progressively developed. The imbalance between ROS production and the natural antioxidant forces has been coined “oxidative stress” by Sies in 1985 [1].

During physiological conditions, basal levels of ROS are generated by all organisms. In mitochondria, a significant fraction of bimolecular oxygen (O2) is incompletely reduced and appears as ROS such as superoxide (O2•), the hydroxyl radical (•OH) and hydroxyperoxide (H2O2). Those ROS are counterbalanced by natural enzymatic antioxidants (superoxide dismutase, catalase…) and non-enzymatic antioxidants (uric acid, ascorbic acid…). In pathological conditions elevated levels of ROS produced by inflammatory processes and mitochondria respiratory chain dysfunction overwhelm natural antioxidant defenses and lead to oxidative stress.

The key effector molecule in oxidative stress is peroxynitrite (oxoperoxonitrate [− 1]: ONOO–) formed by the reaction of nitric oxide (•NO) with superoxide. Nitric oxide is an essential biological molecule produced by neuronal nitric oxide synthase (nNOS) in neurons and by endothelial nitric oxide synthase (eNOS) in endothelial cells during physiological conditions. Inducible nitric oxide synthase (iNOS) is located in mitochondria and microglia and generates high levels of nitric oxide for extended periods of time during inflammatory processes. Neutrophils and mitochondria produce basal levels of superoxide that are markedly increased during respiratory chain dysfunction. Nitric oxide is an essential biological molecule with unique properties that allow it to be used for local signaling in virtually every organ. Nitric oxide is reported to have many toxic effects more likely mediated by its oxidation products rather than nitric oxide itself. Indeed, when nitric oxide is produced in large amounts, it rapidly reacts with superoxide to form peroxynitrite [2] in equilibrium with peroxynitrous acid (ONOOH).

Peroxynitrite reacts with a bewildering number of molecules and remained a chemical curiosity for long. The detection of life on Mars by the Viking mission was likely confronted by the ultra-violet peroxynitrite formation in nitrate found in the Martian soil [3] and addition of peroxynitrite reduces the amount of glass to be used to entrap trans-uranium elements during radioactive waste storage [4]. The biological role of peroxynitrite in endothelial injury was first demonstrated by Beckman in 1990 [5]. The mechanisms of peroxynitrite toxicity are complex [6]. The peroxynitrite anion rapidly reacts with carbon dioxide (CO2) to form the carbonate radical (CO3•‾), a potent oxidant, and nitrogen dioxide (•NO2‾), a strong nitrating agent. Peroxynitrous acid forms the hydroxyl radical and nitrogen dioxide. Importantly, the toxicity of the hydroxyl radical is limited by reacting with too many irrelevant biological targets. The most toxic radicals are thus nitrogen dioxide and the carbonate radical.

It has become to be accepted that peroxynitrite is the final, common toxic effector molecule responsible for oxidative stress damage in almost all pathological conditions including cardiac and vascular diseases, autoimmune local inflammation, brain and spinal cord injury, diabetes and diabetes complications and lastly ND and MS [6] and [7].

Given its very short life, peroxynitrite cannot be identified in biological fluids or tissues. However it nitrates tyrosine residues forming nitrotyrosine (NT) that can be identified immunohistochemically and is commonly used as a foot-print of peroxynitrite. The participation of peroxynitrite to immune-mediated inflammatory diseases was demonstrated in experimental allergic encephalomyelitis (EAE). Peroxynitrite is formed very early and correlates with disease activity [8]. The predominant role of peroxynitrite over nitric oxide is reflected by the efficacy in the EAE model of catalysts specifically neutralizing peroxynitrite and leaving nitric oxide intact [9]. Interestingly oligodendrocytes are resistant to nitric oxide but exquisitely sensitive to peroxynitrite [10]. Lastly, injections of a spontaneous donor of peroxynitrite into the corpus callosum in rats produces myelin destruction and lesions similar to that observed in MS plaques [11]. The multiple mechanisms mediating peroxynitrite toxicities have been recently reviewed [12]. Most of them are likely involved in MS but membrane channel inhibition, calcium dysregulation, protein nitration and lipid peroxidation as well as mitochondrial dysfunction certainly play a major role.

The presence of peroxynitrite has been consistently demonstrated in acute and chronic active MS lesions [13], [14] and [15]. In contrast, peroxynitrite was not detectable in chronic inactive lesions [16]. Interestingly, high levels of peroxiredoxin V, a natural enzymatic antioxidant, have been recently detected in normal appearing white matter from patents with MS, particularly in hypertrophic reactive astrocytes, not only in acute but also in chronic lesions [17]. This suggests that there is on-going oxidative stress in chronic lesions despite the absence of pathologically apparent inflammation. In contrast an elevated expression of myeloperoxidase in microglia was found in acute but not in chronic cortex demyelinating lesions [18].

The role of oxidative stress in MS is also supported by the correlation of Gd-enhancing lesions and of neurofilament damage markers with raised levels of nitric oxide metabolites in the cerebrospinal fluid (CSF) from MS patients [19] and [20].

3. Excitotoxicity
Neuronal death caused by excessive exposure to excitatory amino acids (EAA) was first described by Olney in 1978 [21]. Excitotoxicity is the result of an imbalance between excitatory processes due to glutamate overload and inhibitory processes mediated by GABA and glycine.

Glutamate is the major EAA for the development of synaptic connections and of neurological functions. Physiological concentrations are close to that destroying neurons and extracellular levels are precisely controlled. The mammalian brain is extraordinary vulnerable to its own neurotransmitters.

Glutamate overload most frequently results from the glutamate–glutamine cycle dysfunction. In physiological conditions, astrocytes take up glutamate from the extracellular spaces via EAA transporters and convert it to glutamine via ATP dependent mechanisms. In turn, neurons take up glutamine released by astrocytes in extracellular spaces and convert it back to glutamate via glutaminase.

In many pathological conditions ATP depletion causes astrocyte dysfunction, increased intracellular glutamate, inward transporter reversal and extracellular glutamate overload. Other causes of increased levels of glutamate are presynaptic vesicular release, leak from injured cells and EEA receptor dysfunction. The mechanisms of excitotoxicity are complex. In short, EAA receptors are coupled to ionic channels and their dysfunction activates a chain of events leading to channellopathy, calcium overload, mitochondriopathy, proteolytic enzyme production and activation of pathways leading to cell apoptosis. In addition, it has long been established that excitoxicity mediates peroxynitrite production [22] and conversely, that peroxynitrite elicits excitotoxicity [23]. This complex interplay of inflammation and excitotoxicity leads to auto-toxic loops described in ND and possibly involved in MS [24].

The potential role of exitotoxicity in MS was first suggested by experimental data demonstrating the beneficial effect of NMDA and AMPA/Kainate blockers in EAE [25] and the reduction of axonal and oligodendrocyte damage [26], [27] and [28]. Interestingly, over-activation of glutamate receptors caused MS-like histopathological lesions [29]. Neurons are exquisitely sensitive to excitotoxicity [30] and kainate activation sensitizes oligodendrocytes to complement toxicity [31]. Exicitotoxicity damages myelin but axons appear more resistant [32]. Lastly, excitotoxicity contributes to blood brain barrier (BBB) dysfunction via endothelial cell EAA receptors damage [33].

In MS lesions, immunochemistry show axonal damage co-localized with strongly glutamate positive cells [34]. Glutamate transporter-1 and glutamine synthase are down-regulated in oligodendrocytes surrounding active lesions [35] whereas glutamate receptors are up-regulated [36]. The loss of EAA transporters in cortical lesions correlates with microglial activation, demyelination and synaptic damage [37].

4. Discussion
Inflammation, oxidative stress and excitotoxicity cause neuron degeneration and death in ND such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) and are also clearly involved in MS. Emerging evidence strongly suggests that inflammation, and in particular microglial activation, is a common initial event triggered in MS by an autoimmune reaction and in neurodegenerative diseases by protein misfolding: β-amyloid in AD, α-synuclein in PD and neurofilaments in ALS [38]. Whatever the cause, microglia activation releases a large variety of proinflammatory mediators initiating the inflammatory cascade on the one hand, and the degenerative cascade including oxidative stress and excitotoxicity on the other hand. In addition, as previously mentioned, there is a complex interplay of those three pathological processes that makes therapeutic approaches more difficult (Fig. 1).



Full-size image (40K)


Fig. 1. PATHOMECHANISMS in MS and neurodegenerative diseases.


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The question arises whether there are some differences between degenerative mechanisms in MS and ND. A recent paper shows that profound microglia activation was found both in MS and AD with a similar activation pattern. However, meningeal T and plasma cell infiltration correlated with microglia activation in MS but not in AD. Microglia activation appears to be driven by innate immunity in AD and by adaptive immune responses in MS [39]. Of note that microglia activation does not favor the development of amyloid plaques even though peroxynitrite induces Alzheimer-like tau modifications experimentally [40]. Inflammation has also received increased attention in ND recently [41] but inflammatory processes clearly predominate in MS.

Considerable efforts are made to develop new drugs against neurodegeneration and the main potential therapeutic targets counteracting pathological mechanisms of oxidative stress and excitotoxicity are listed in Table 1. As other papers presented here concern inactivation of microglia and channel blockers, we will limit this review to peroxynitrite catalysts and natural antioxidants.


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Table 1.

Main therapeutic targets in oxidative stress and excitotoxicity

Microglial inactivation
Oxidative stress
inhibitors of ONOO− precursors: iNOS, •NO, O2•−, OH−peroxynitrite catalysts
ONOO− derived free radical scavengers
natural anti-oxidants: enzymatic non-enzymatic
Excitotoxicity
NMDA, AMPA/Kainate antagonists
Ca+ overload antagonists
Na or K channel blockers
Mitochondrial protection and anti-apoptotic factors
Full-size table

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The central role of peroxynitrite in oxidative stress and excitotoxicity makes it an interesting therapeutic approach. Therapeutic modulation of its precursors such as inducible NOS, nitric oxide or superoxide appears delicate and yielded only modest and contradictory results in EAE [42]. The likely reason is the dual role of nitric oxide according to the microbiological environment.

The mechanisms of peroxynitrite decomposition are not completely elucidated [12] but the aim is to divert peroxynitrite decomposition to harmless molecules and avoid the formation of the most two relevant toxic ROS: nitrogen dioxide and the carbonate radical. Several iron and manganese porphyrins were found effective peroxynitrite catalysts in experimental models of autoimmune diseases notably EAE. The iron porphyrin FP15 out-competes with the peroxynitrite reaction with carbon dioxide preventing carbonate radical formation. FP15 down-regulates inflammatory and cell-death pathways and protects cultured neuron against NMDA exposure. Another iron porphyrin, INO-4885 (formerly WW85) decreases protein nitration, lipid peroxidation and poly (ADP-ribose) polymerase activation. Human safety trials are in progress. A manganese porphyrin, AEOL 10150, a superoxide dismutase mimetic scavenges the carbonate radical. It protects mitochondria against peroxynitrite damage. This molecule is under clinical development in ALS [43] and [44].

To prevent oxidative damages due to oxygen catabolism, natural antioxidant defenses have been integrated during species evolution. The neuroprotective experimental and clinical activity of natural (enzymatic or non-enzymatic) antioxidants has been discussed elsewhere [24]. We will thus restrict our concern to antioxidant enzyme up-regulation and to the potential interest of uric acid.

Most of endogenous antioxidants do not cross the BBB and administration of large amounts is required to achieve effective CNS levels. In ND and in MS, the expression of several antioxidant enzymes is regulated by the nuclear factor erythroid-2 related factor (Nrf2) that activates the antioxidant response element (ARE) in the promoter of antioxidant genes [45] and [46]. The activation of this mechanism likely reflects an on-going oxidative stress in MS [47]. It is notable that peroxynitrite depletes natural antioxidant glutathione (GSH) via a reduction in the Nrf2 that down-regulates the expression of glutamate systeine ligase, the rate limiting enzyme for GSH [48]. Specific enzyme inducers or viral vectors were found effective to up-regulate Nrf2 and enhance production of hemeoxygenase-1 and catalase as well as to reduce EAE symptoms [49] and [50]. Several agonists of Nrf2 could potentially be of therapeutic interest notably dimethylfumarate [51], fibroblast growth factor and nerve growth factor [52] as well as BG0012, a fumaric acid derivative that was found to significantly reduce Gd+ lesions in RR MS [53] and is currently investigated in two phase II trials [54].

Uric acid (UA) is the major natural antioxidant in humans. Inactivation of the uricase gene is considered as an evolutionary advantage and led to UA serum levels 10 times higher than in other mammals [55]. Uric acid does not scavenge peroxynitrite but inactivates free radicals, in particular nitrogen dioxide and the carbonate radical, before they react with their targets [56]. It reduces protein nitration and lipid peroxidation and protects DNA from oxidative damage [57].

Uric acid is definitely more effective in EAE than other natural antioxidants [58] and inhibits CNS inflammation, BBB dysfunction and tissue damage [59]. Uric acid reduces glutamate-stimulated peroxynitrite production [60] and induces up-regulation of EAA transporters on astrocytes favoring protection against excitotoxicity [61]. Ischemic preconditioning is partly mediated by UA [62]. Of note that UA does not interfere with the immune system, in particular it has no effect on Ag presentation and T cell activation or proliferation [63].

The neuroprotective activity of UA has been demonstrated in spinal cord injury [64] and [65] and in acute brain ischemia [66] and [67]. Altered UA levels are observed in several disease states [68] and considerable evidence has accumulated that UA could play a role in MS. Serum UA levels were found lower in patients with MS and in mono- or dizygotic twins than in healthy controls [69] or healthy twins [70] as well as in patients with optic neuritis [71]. With regard to other neurological diseases (OND) differences appear more complex. Uric acid serum levels in MS patients were found lower than in those with vascular pathology. In contrast, serum levels in patients with cryptococcus and tuberculous meningitis were lower than in MS patients, whereas no major difference was noted in comparison with most OND [72].

Lower levels of UA in patients with PD [73] and AD [74] have been reported. In contrast high serum UA levels correlate with a reduced risk of PD [75] and [76] and epidemiological studies have shown that patients with a previous history of gout are at lower risk to develop MS [69] and PD [77]. Lower serum UA levels during disease activity remains debated but most publications are in favor of a positive correlation [78], [79], [80], [81] and [82]. Increased serum UA levels were found in patients with MS treated with high doses of methylprednisolone [83], glatiramer acetate [84] and IFNβ [85] suggesting that hyperuricemia participates, at least in part, to the clinical benefit.

Given its destruction by uricase in gut, oral administration of UA does not modify serum levels but oral administration of precursors of UA (inosine or inosinic acid) increases UA levels both in serum and in CSF [86]. An open-label study of inosine in RR MS vs matched untreated patients suggests a benefit on relapse rate and on disability progression [87]. Two phase II trials with inosine are in progress: one with inosine as a single agent vs placebo [88], the second with inosine + IFNβ vs inosine + placebo [89]. Those proof of concept studies will hopefully answer the question whether antioxidant strategies might be efficacious in MS.

5. Conclusion
There is increasing awareness that neurodegeneration is an integral part of MS pathomechanisms. Neurodegenerative processes have been extensively investigated in ND and the central question arises whether they are the same in MS. Microglia activation appears the common initial event in both disease states. It is generally believed that microglia activation is mediated by adaptive immunity in MS but recent observations suggest that innate immunity is sufficient to activate microglia in a subset of patients [90]. In contrast, there is compelling evidence that microglia activation is caused by aberrant protein aggregation in ND.

It has been recently observed that microglia activation correlates with important meningeal lymphocyte and plasma-cell infiltrates in MS but not in AD [39]. In most MS patients microglia activation is clearly associated with cellular infiltration but of course there is no information about pathological lesions at the very early disease onset, during the subclinical phase. Recent observations in patients with fulminant MS deceased shortly after a relapse show that the earliest structural changes in newly forming lesions are microglial activation in absence of lymphocyte infiltration. This suggests that microglia activation could be the initiating event in MS leading to the inflammatory cascade on the one hand and to the degenerative cascade (oxidative stress and excitotoxicity) on the other hand. In contrast, in ND cellular infiltration is usually very discrete.

This marked inflammatory component in the RR phase of MS is important for the design of therapeutic strategies. Inflammation not only causes early neuronal and axonal loss but also initiates the degenerative cascade that contributes to neural tissue damage. One may suspect that potent anti-inflammatory agents now available can block inflammatory processes, reduce associated degenerative mechanisms and subsequently delay the development of neurodegeneration. This assumption is supported by the results of the trial with alemtuzumab in early RR MS that demonstrate that not only disability progression is stopped but that neurological deficits are improved in most patients [91] and [92].

During the SP phase, inflammatory processes are compartmentalized in meninges and neurodegenerative processes predominate. So far, clinical trials to protect CNS against neurodegeneration led to inconclusive results. Inflammation is mainly mediated by cellular immune components that can be modulated by cytotoxic agents or drugs regulating lymphocyte trafficking. In contrast, neurodegeneration is caused by multiple and intertwined biochemical systems operating via alternate pathways. So far the translation of experimental results with neuroprotective drugs has been disappointing and led to modest efficacy like riluzole in MS [93] and even in negative effects such as minocycline in ALS [94] P.H. Gordon, D.H. Moore, R.G. Miller, J.M. Florence, J.L. Verheijde and C. Doorish et al., Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial, Lancet Neurol 6 (2007), pp. 1045–1053. Article | PDF (212 K) | View Record in Scopus | Cited By in Scopus (43)[94]. Most drugs in development for ND are too specific and aimed at a particular target. Modulating a single specific pathway in diseases characterized by parallel mechanisms will likely yield a partial benefit if any. The contrasting roles of inflammatory components as well as degenerative components may also explain this modest efficacy. Microglia definitely induce and sustain inflammation but sense danger signals and can restore CNS integrity [95]. Most importantly, altering physiological signal can lead to unexpected effects. In EAE, sudden withdrawal of phenitoin resulted in acute exacerbation and increased permeability of the BBB [96]. Targeting proximal upstream events initiating the degenerative cascade such as peroxynitrite might thus be more rewarding.

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痛风减少细胞介导的自免性疾病机制

Burton Abrams, a,

a221 Linden Drive, Elkins Park, PA 19027, United States


Received 6 August 2008; accepted 9 August 2008. Available online 25 September 2008.

Article Outline
References
Gout has been reported to have an unusually low coincidence with rheumatoid arthritis (RA) [1], systemic lupus erythematosus [2], and Parkinson’s disease [3]. RA and lupus have been established as autoimmune. Parkinson’s was hypothesized recently to be autoimmune [4]. This correspondence hypothesizes the physiological mechanism by which gout inhibits the development of these and other cell-mediated autoimmune diseases.

Gout and cell-mediated autoimmune disease have both been reported as consequences of sleep apnea, a gout flare within a few hours [5] and cell-mediated autoimmune disease over the long term [6]. The prevalence of sleep apnea in at least the mild form has been estimated to be 20% of the adult population in western countries [7], a much higher prevalence than gout or any autoimmune disease.

As described in [5] and [6], both conditions can result from the effects on the immune system of monosodium urate crystals (MSU), which precipitate as a result of the catabolic hyperuricemia and pulmonary acidosis caused by the frequent hypoxic intervals of sleep apnea. Once formed, even with a desirable serum uric acid concentration <6 mg/dl, MSU crystals have an half-life of many months before they are finally dissolved [8].

Most people with sleep apnea are not predisposed to gout, even though many of them precipitate MSU into nonsynovial connective tissue. In those not predisposed to gout, the MSU continues to up-regulate the immune system for many months by the maturation of dendritic cells and T cells [9], thereby increasing the likelihood of autoimmune development. Those who are predisposed to gout shield the MSU crystals from long-term sensing by MSU-activated dendritic cells, either by encasing the MSU crystals in tophi or by coating them while in synovium with a protein, primarily apo E which originates in synovium [10]. As a result of this protein coating, the duration of a single gout flare is typically only 3 to 10 days. It is also the hypothesized mechanism by which gout inhibits the development of those cell-mediated autoimmune diseases that result from the hypoxia of sleep apnea.

A consequence of this hypothesis may be that other diseases whose coincidence with gout are found to be unusually low but have not been recognized as autoimmune, should be suspected as being autoimmune. This recognition can lead to new understanding and new treatments for these diseases. Most importantly, individuals evidencing these diseases should be screened for sleep apnea and then treated appropriately.

References

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尿酸与PD的认知

Cognitive dysfunction is common in Parkinson's disease (PD). Low plasma uric acid level is a risk factor for PD but its association with cognitive impairment in PD has not been previously studied. In the present study urine uric acid level as well as plasma uric acid- and homocysteine levels were measured in 40 patients with PD. Comprehensive neuropsychological tests including computerized tasks were performed on all. Both low plasma and low urine uric acid levels associated with decreased neuropsychological performance. In multiple linear regression low urine uric acid level predicted worse performance in the Picture completion subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (p = 0.003) and in the Rule shift cards test of the Behavioral Assessment of the Dysexecutive Syndrome (BADS) (p = 0.04). Low plasma uric acid level predicted worse performance both in the Picture completion (p = 0.02) and Similarities subtest of the WAIS-R (p = 0.02). Reaction time and the time spent on cognitive processing in the Statement verification task were inversely correlated with the uric acid levels (p = 0.0001). There was no correlation between the homocysteine level and neuropsychological performance. Instead, the plasma uric acid and homocysteine levels correlated significantly and their possible association in PD is discussed.
Keywords: Uric acid; Homocysteine; Cognition; Parkinson's disease
Article Outline

1. IntroductionSubtle cognitive changes are often detected early in Parkinson's disease (PD) [1] and poor initial performance on neuropsychological tests measuring verbal fluency [2] and in the Picture completion subtest of the WAIS-R [3] have been shown to predict subsequent dementia. The reasons for cognitive decline in PD are unclear though several risk factors have been identified [1] and [4].
Low plasma uric acid level has been found to be a risk factor for PD [5], but its association with cognition has not been previously studied in PD. In the present study we measured plasma and daily urine uric acid concentrations in PD patients and assessed their cognition with comprehensive neuropsychological testing. The associations of the uric acid levels with cognitive changes and plasma homocysteine were examined.
2. Materials and methods
The characteristics of the study population (40 PD patients, mean age 60.8 years, 23 men and 17 women with post-diagnostic disease duration not more than 10 years) have been described previously in detail [6]. All patients signed a written informed consent. The study was approved by the Ethics Committee of Helsinki and Uudenmaa Health District Area. The neuropsychological testing and the laboratory sampling took place from February to October 2005.
The plasma uric acid levels were assessed from fasting blood samples and urine uric acid concentrations from 24 h samples with an enzymatic assay in the Laboratory of Helsinki and Uudenmaa Health District (HUSLAB) as described. Plasma homocysteine levels were assessed with immunochemiluminometric method.
The neuropsychological test battery included both traditional neuropsychological tests and computerized tasks from the CogniSpeed for Windows 1.0 software. Depression was assessed with the Beck Depression Inventory (BDI). Education was classified into three categories; primary school only, secondary school and college. General cognitive status was assessed with the Mini Mental State Examination (MMSE) and the Information and Similarities subtests of the WAIS-R. Visuospatial and visuoconstructive functions were assessed with the Picture completion and Block design subtests of the WAIS-R. The Digit span and Digit symbol subtests of the WAIS-R, the Logical memory subtest of the Wechsler Memory Scale-Revised (WMS-R), the Word list subtest of the Wechsler Memory Scale-Third Edition (WMS-III) and the Visual reproduction subtest of the WMS-R were used to assess working memory, verbal learning and memory and visual learning and memory, respectively. Executive functions were assessed with the Trail making and Rule shift cards tests from the Behavioral Assessment of the Dysexecutive Syndrome (BADS). Verbal fluency was assessed with asking the subject to list as many animals in a minute as he/she could and then words that begin with the letter K.
Computerized tasks included Simple Reaction Time (SRT), Two-choice Reaction Time (2-CRT) and Ten-choice Reaction Time (10-CRT). Subtraction-, Statement verification- and Stroop-type tasks were used to assess controlled cognitive processing and Vigilance task to measure attention.
The results were analyzed with SPSS for Windows 13th edition. Logarithmic and X2 transformations were used to normalize non-parametric data if applicable. In multiple linear regression, each neuropsychological test score was used as the dependent variable in a separate equation. To consider the factors possibly contributing to cognitive performance, age, gender, Body Mass Index (BMI), education, disease duration from diagnosis, levo-dopa therapy (yes/no), BDI, plasma homocysteine and either plasma or urine uric acid were used as explanatory variables. If there were two or more significant explanatory variables, hierarchical regression was applied to assess the relative importance of the variables.
3. Results
The median (range) plasma uric acid level was 287.5 mmol/l (153–467), urine uric acid level was 3.2 mmol/l (1.1–5.8) and homocysteine level was 9.3 μmol/l (6.4–21.6). Plasma uric acid level correlated with urine uric acid (r = 0.4, p = 0.02) and homocysteine (r = 0.40, p = 0.01) levels. The cognitive scores did not correlate with plasma homocysteine but several correlations with the uric acid levels were observed (Table 1).

As expected, education correlated with several neuropsychological parameters whereas gender, disease duration from diagnosis and levo-dopa therapy had few occasional correlations and BMI, BDI, hypertension and smoking had none (data not shown). In a forward multiple linear regression using urine uric acid and the other explanatory variables given in Section 2, urine uric acid was the only variable contributing to the Picture completion subtest (F = 10.1, R2 = 0.21, p = 0.003). Urine uric acid was also the only variable predicting both reaction time and the time spent on cognitive processing in the Statement verification task (F = 16.5, R2 = 0.31, p = 0.0001; F = 17.3, R2 = 0.33, p = 0.0001, respectively). Urine uric acid and education predicted the Rule shift cards score (F = 4.6, R2 = 0.20, p = 0.02), uric acid accounting for 11% (p = 0.04) of the total variation. Urine uric acid and BDI predicted the Block design subtest score (F = 6.7, R2 = 0.27, p = 0.003), urine uric acid accounting for 17% (p = 0.01) of the total variation. Female gender predicted low Similarities subtest score (F = 7.3, R2 = 0.17, p = 0.01). Education was found to contribute significantly to the Backward digit span score (F = 5.2, R2 = 0.12, p = 0.03).
When plasma uric acid was substituted for urine uric acid in the multiple regression equation, gender and education were found to contribute significantly to the Picture completion subtest (F = 5.5, R2 = 0.31, p = 0.003). Plasma uric acid and education contributed to the Similarities subtest (F = 5.7, R2 = 0.24, p = 0.007). Plasma uric acid's independent contribution was 14% (p = 0.02) and 13% (p = 0.02), respectively. In the Statement verification task plasma uric acid and education were found to be significant predictors (F = 6.2, R2 = 0.26, p = 0.005), while uric acid alone contributed for 15% (p = 0.02) of the variation. The time required for cognitive processing during the task depended on plasma uric acid level and education (F = 7.6, R2 = 0.3, p = 0.002); uric acid's contribution was 13% (p = 0.02).
4. Discussion
The present study shows that low plasma and urine uric acid levels associate with worse cognitive performance in PD. The finding is in accordance with the view that uric acid has neuroprotective properties, probably due to its action as both an antioxidant and iron chelator [7]. The Picture completion and Block design subtests are considered sensitive to subcortical damage, as they require both visuospatial and visuoconstructive abilities, sustained attention and good executive control. The Similarities subtest measures verbal skills and concept formation, abilities known to associate with involvement of left temporal and frontal regions, areas that show diminished activity also in PD. The Rule shift cards- and the Statement verification task are both measures of executive function, often impaired in PD patients.
Serum homocysteine is the only molecule that has been connected to cognitive impairment in PD [8]. Our study, as well as others [9], found a correlation between plasma homocysteine and uric acid levels. This connection remains unexplained but it has been hypothesized that adenosine and methylenetetrahydrofolate produced during the homocysteine synthesis would be used for producing uric acid [10], possibly to protect the body from the harmful effects of homocysteine. Plasma uric acid level may be even more sensitive than homocysteine to cognitive changes in PD. This may explain why no correlations were observed between the homocysteine levels and neuropsychological scores in a small sample size.
In a recent paper, Schretlen et al. found high serum uric acid level being detrimental to cognition in a community sample of healthy volunteers [11]. The mechanism of cognitive impairment was hypothesized to be cerebrovascular. Our results show an opposite association between uric acid level and cognitive state but Schretlen et al. excluded individuals with PD in their study. In PD the cognitive changes correlate strongly with the pathological state [12] and are thus a direct consequence of the underlying disease process. Given that uric acid has a protective function in PD, it is plausible that uric acid plays a different role in PD than in healthy individuals.
Our study contains some considerable confounders. The study population, although well defined, was relatively small. Also, the observed correlation between the uric acid levels and neuropsychological test scores may not be specific for PD. Low plasma uric acid level has been observed in Alzheimer's disease [13] and vascular dementia [14], but there is no data on correlations to neuropsychological test results in these patient groups. Our study was lacking a control group but considering the information on healthy older adults [11], our results suggest that uric acid may play a more important role in the pathophysiology of neurodegenerative disorders than expected.
Our study is the first to show a connection between plasma and urine uric acid levels and cognitive impairment in PD. Further studies are needed to establish if low uric acid level predisposes to dementia in PD.

Acknowledgements
The study was supported by Jorvi Hospital Science Fund. We thank Dr. Marjatta Pohja for her comments on the manuscript.

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