The lived experience of severe mental illness and long-term conditions: a qualitative exploration of service user, carer, and healthcare professional perspectives on self-managing co-existing mental and physical conditions.

BACKGROUND: People with severe mental illness (SMI), such as schizophrenia, have higher rates of physical long-term conditions (LTCs), poorer health outcomes, and shorter life expectancy compared with the general population. Previous research exploring SMI and diabetes highlights that people with SMI experience barriers to self-management, a key component of care in long-term conditions; however, this has not been investigated in the context of other LTCs. The aim of this study was to explore the lived experience of co-existing SMI and LTCs for service users, carers, and healthcare professionals. METHODS: A qualitative study with people with SMI and LTCs, their carers, and healthcare professionals, using semi-structured interviews, focused observations, and focus groups across the UK. Forty-one interviews and five focus groups were conducted between December 2018 and April 2019. Transcripts were coded by two authors and analysed thematically. RESULTS: Three themes were identified, 1) the precarious nature of living with SMI, 2) the circularity of life with SMI and LTCs, and 3) the constellation of support for self-management. People with co-existing SMI and LTCs often experience substantial difficulties with self-management of their health due to the competing demands of their psychiatric symptoms and treatment, social circumstances, and access to support. Multiple long-term conditions add to the burden of self-management. Social support, alongside person-centred professional care, is a key facilitator for managing health. An integrated approach to both mental and physical healthcare was suggested to meet service user and carer needs. CONCLUSION: The demands of living with SMI present a substantial barrier to self-management for multiple co-existing LTCs. It is important that people with SMI can access person-centred, tailored support for their LTCs that takes into consideration individual circumstances and priorities.

Empirically derived formulae for calculation of age- and region-related levels of iron, copper and zinc in the adult C57BL/6 mouse brain.

Metal dyshomeostasis is associated with neurodegenerative disorders, cancers and vascular disease. We report the effects of age (range: 3 to 18 months) on regional copper, iron and zinc levels in the brain of the C57BL/6 mouse, a widely used inbred strain with a permissive background allowing maximal expression of mutations in models that recapitulate these disorders. We present formulae that can be used to determine regional brain metal concentrations in the C57BL/6 mouse at any age in the range of three to eighteen months of life. Copper levels in the C57BL/6 mouse adult brain were highest in the striatum and cerebellum and increased with age, excepting the cortex and hippocampus. Regional iron levels increased linearly with age in all brain regions, while regional zinc concentrations became more homogeneous with age. Knockdown of the copper transporter Ctr1 reduced brain copper, but not iron or zinc, concentrations in a regionally-dependent manner. These findings demonstrate biometals in the brain change with age in a regionally-dependent manner. These data and associated formulae have implications for improving design and interpretation of a wide variety of studies in the C57BL/6 mouse.

Substantia nigra echomorphology and motor cortex excitability.

The aim of our study was to investigate the relation between substantia nigra (SN) echomorphology and indices of motor cortex excitability. Nigral hyperechogenicity in healthy individuals is thought to represent an SN abnormality or predisposition to Parkinson's disease (PD) and its prevalence is greater in the very old. Our study involved 20 old healthy subjects (aged 72-84 years) known to have normal (n=10) or abnormal (n=10) SN echomorphology. All were in good health with no overt neurological signs. SN morphology was assessed with transcranial sonography through the pre-auricular bone window. Motor cortical excitability and intracortical inhibition were assessed with transcranial magnetic stimulation (TMS) over the first dorsal interosseus motor area. Single stimuli were delivered during relaxation and voluntary contraction and paired stimuli were delivered during relaxation. Each cortical hemisphere was analysed separately. The response to single-pulse TMS (in motor cortex ipsilateral to the target SN) did not differ between groups. However, a significant difference between groups was observed in the paired pulse paradigm (conditioning stimulus intensity: 70% resting motor threshold; interstimulus interval: 2 ms). The conditioned motor evoked potential amplitude was significantly larger ipsilateral to the hyperechogenic SN than in controls (P=0.014). Thus, healthy subjects with SN hyperechogenicity exhibit significantly less intracortical inhibition within the motor cortex than subjects with normal echomorphology. Decreased intracortical inhibition is also observed in PD patients. This study provides further evidence that SN hyperechogenicity in healthy individuals is associated with changes characteristic of PD supporting a role for this feature as a vulnerability marker or state marker for subtle nigral dopaminergic dysfunction.

Lipid content determines aggregation of neuromelanin granules in vitro.

The neuromelanin pigment of the substantia nigra of the human brain is closely associated with lipids and other non-melanogenic compounds which appear to contribute to the unique and complex morphology of neuromelanin pigment granules. In this work we show that insoluble granules isolated from the human substantia nigra associate in vitro to form pigment aggregates similar to those present in the human brain. Extraction of neuromelanin-associated polar lipids by methanol and/or hexane significantly enhanced melanin aggregate size. A marked (10-fold) increase in granule size was seen after methanol treatment, whereas the application of hexane after methanol reduced this pro-aggregation effect. We have previously reported that hexane and methanol remove the neuromelanin-associated polyisoprenoids dolichol and cholesterol respectively. Thus, the current data suggests that pigment-associated lipids may be a factor regulating pigment aggregation and neuromelanin granule size in vivo.

Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson's disease.

Neuromelanin (NM) is a dark polymer pigment produced in specific populations of catecholaminergic neurons in the brain. It appears in greatest quantities in the human brain, in lesser amounts in some other non-human primates, but is absent from the brain in many lower species. Interest in this pigment has seen a resurgence in recent years because of a hypothesised link between neuromelanin and the especial vulnerability of neuromelanin-containing neurons to cell death in Parkinson's disease (PD). Little is known regarding the biology of neuromelanin. As neuromelanin appears to have characteristics in common with the better studied peripheral melanin pigments this review compares what is known about neuromelanin with melanins found in other body tissues. Unlike peripheral melanins, which are produced in specialised cells called melanocytes and may be transferred to other cell types, neuromelanin granules are believed to be stored in the cell in which they are produced. Neuromelanin granules display a unique, more heterogeneous appearance compared with peripheral melanins. Unlike melanin, neuromelanin is traditionally thought to result from a non-enzymatic synthesis pathway with no known pathway for neuromelanin catabolism. More recent data, however, is indicative of some regulation of neuromelanin synthesis and turnover. By analogy with peripheral melanins, neuromelanin may function in vivo to attenuate the effects of damaging stimuli. Among several possible mechanisms suggested, the ability of neuromelanin to interact with transition metals, especially iron, and to mediate intracellular oxidative mechanisms has received particular attention. Recent data from neuromelanin in the Parkinson's disease brain suggests that this proposed function may be compromised, thus rendering pigmented neurons vulnerable to oxidative damage in this disorder.

Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain.

The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment-responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine action.

Evidence for specific phases in the development of human neuromelanin.

Neuromelanin is a dark-coloured pigment which forms in the dopamine neurons of the human midbrain. The age-related development and regulation of neuromelanin within these dopamine neurons has not been previously described. Optical density and area measurements of unstained neuromelanin in ventral substantia nigra neurons from 29 people spanning the ages of 24 weeks to 95 years old, demonstrated three developmental phases. Neuromelanin was not present at birth and initiation of pigmentation began at approximately 3 years of age, followed by a period of increasing pigment granule number and increasing pigment granule colouration until age 20. In middle and later life the colour of the pigment granules continued to darken but was not associated with any substantial growth in pigment volume. The identification of three phases and changes in the rate of neuromelanin production over time suggests the regulation of neuromelanin production and turnover, possibly through enzymatic processes.

New face of neuromelanin.

The massive, early and relatively circumscribed death of the dopaminergic neurons of the substantia nigra in Parkinson's disease has not yet been adequately explained. The characteristic feature of this brain region is the presence of neuromelanin pigment within the vulnerable neurons. We suggest that neuromelanin in the Parkinson's disease brain differs to that in the normal brain. The interaction of neuromelanin with iron has been shown to differ in the parkinsonian brain in a manner consistent with an increase in oxidative stress. Further, we suggest an interaction between the lipoprotein alpha-synuclein and lipidated neuromelanin contributes to the aggregation of this protein and cell death in Parkinson's disease. The available data suggest that the melaninisation of the dopaminergic neurons of the substantia nigra is a critical factor to explain the vulnerability of this brain region to early and massive degeneration in Parkinson's disease.

Potential sources of increased iron in the substantia nigra of parkinsonian patients.

Histopathological, biochemical and in vivo brain imaging techniques, such as magnetic resonance imaging and transcranial sonography, revealed a consistent increase of substantia nigra (SN) iron in Parkinson's disease (PD). Increased iron deposits in the SN may have genetic and non-genetic causes. There are several rare movement disorders associated with neurodegeneration, and genetic abnormalities in iron regulation resulting in iron deposition in the brain. Non-genetic causes of increased SN iron may be the result of a disturbed or open blood-brain-barrier, local changes in the normal iron-regulatory systems, intraneuronal transportation of iron from iron-rich area into the SN and release of iron from intracellular iron storage molecules. Major iron stores are ferritin and haemosiderin in glial cells as well as neuromelanin in neurons. Age- and disease dependent overload of iron storage proteins may result in iron release upon reduction. Consequently, the low molecular weight chelatable iron complexes may trigger redox reactions leading to damage of biomolecules. Additionally, upon neurodegeneration there is strong microglial activation which can be another source of high iron concentrations in the brain.

Identifying severely atrophic cortical subregions in Alzheimer's disease.

The present study analyses the pattern of atrophy in anatomically discrete brain regions in prospectively-studied pathologically-confirmed patients with Alzheimer's disease (AD) and controls. Standard volumetric measurements were made of the entire cortex subdivided into 23 anatomical regions. Analyses determined regions of significant atrophy in AD and differences between the severity and rates of atrophy. Two levels of severity were found. Atrophy concentrated in medial temporal lobe structures as well as in inferior temporal and superior and middle frontal cortices. The degree of atrophy in these regions related to disease duration, consistent with an early and sustained disease process. The rate of atrophy was significantly greater for the fusiform gyrus. The inferior frontal lobes were entirely spared at all AD stages, while atrophy of other cortical regions was less marked and not related to disease duration, suggesting late involvement. Our findings show that the fusiform gyrus is particularly affected by AD, and suggest two levels of atrophy that correspond with published neurofibrillary tangle (most atrophic) and senile plaque (less atrophic) densities.

Topography of brain atrophy during normal aging and Alzheimer's disease.

The present study investigated the effect of age on total and regional brain volumes and compared age-associated changes in 20 healthy controls with those observed in 12 patients with Alzheimer's disease (AD). Weights and volumes of the whole brain and cerebrum, as well as the fractional volumes of the frontal, temporal, and parieto-occipital cortices, medial temporal structures, deep brain structures, and white matter were measured. Males had larger and heavier brains than females of comparable age. A small decline in brain volume with age was found (approximately 2 ml per year), but only within the white matter. In comparison, no further loss of white matter occurred in AD; however, the cerebral cortex was significantly reduced in volume, with the greatest loss from the medial temporal structures. This loss was related to disease progression; greater proportional loss was associated with more rapid decline in older patients. This study suggests that significant brain atrophy is not a consequence of advancing age. In addition, it suggests a regional specificity of damage in AD.

Language-associated cortical regions are proportionally larger in the female brain.

BACKGROUND: Many studies have demonstrated significant sexual dimorphism in verbal ability. However, few studies have examined anatomical differences between the sexes that may underlie such dimorphism. OBJECTIVE: To examine sex differences in the absolute and proportional volumes of the main language-associated regions of the cerebral cortex. DESIGN AND MAIN OUTCOME MEASURES: Control neuropathological case series of consecutive autopsies from a teaching hospital. No significant age-related volume changes were identified in the sample. Two language-associated cortical regions, the superior temporal gyrus (part of the Wernicke area) and its subdivisions (planum temporale, Heschl gyrus, and anterior superior temporal gyrus) and the inferior frontal gyrus (Broca area in the dominant hemisphere), and a non-language-associated region, the frontal pole, were measured using stereological techniques in brains fixed with formaldehyde solution serially sectioned at 3-mm intervals. Volume comparisons between the sexes and between brain hemispheres were performed using 2-way analysis of variance. SETTING: Studies were conducted at the University of Sydney and the Prince of Wales Medical Research Institute, Sydney, Australia. PATIENTS: Ten males and 11 females free from neurologic or neuropathological abnormalities. RESULTS: The volume of the superior temporal cortex, expressed as a proportion of total cerebral volume, was significantly larger in females compared with males (17.8% increase; P = .04). This was accounted for by 1 section of the superior temporal cortex, the planum temporale, which was 29.8% larger in females (P = .04). In addition, the cortical volume fraction of the Broca area in females was 20.4% larger than in males (P = .05). In contrast, no significant differences were found in the proportional volume of the frontal pole or in regional volumes between the left and right hemispheres in either sex group. CONCLUSIONS: Our results suggest that females have proportionally larger Wernicke and Broca language-associated regions compared with males. These anatomical differences may correlate with superior language skills previously demonstrated in females.

Cell loss in the nucleus basalis is related to regional cortical atrophy in Alzheimer's disease.

Cortical atrophy and cell loss in the cholinergic nucleus basalis is a well-established characteristic of Alzheimer's disease; however, previous studies not have analysed cholinergic cell loss and cortical atrophy in concert. In autopsy brains from eight patients with Alzheimer's disease and 12 control subjects, the numbers of nucleus basalis neurons were determined from 50-microm serial Nissl-stained sections. Volumes of the cerebrum, cortical gray matter (total, lobar and subregional), white matter and deep gray structures were computed by point counting on black and white photographs of gapless 3-mm coronal slices of formalin-fixed brains. Cell loss in the nucleus basalis was found to range between 89% and 42% in Alzheimer's disease compared with controls. White matter volume was unchanged in absolute terms in Alzheimer's disease patients compared with controls, while cortical volume was significantly reduced. Gray matter atrophy was most prominent in temporal and frontal cortices. A highly significant linear relationship was found between cortical volume and nucleus basalis cell number in controls and Alzheimer's disease patients, with values for both groups on a single regression line. Whole brain and cerebral volumes were also highly correlated to nucleus basalis cell numbers in both groups. A quantitative analysis of plaque and tangle burden in cortical target areas of the nucleus basalis was performed. In contrast to the relationship with cortical volume, nucleus basalis cell number and neurofibrillary tangle number were not significantly correlated to the density of cortical histopathology. These results suggest that the volume of cortical gray matter is coupled to the number of nucleus basalis neurons. Compromised viability of nucleus basalis neurons may precede cortical volume loss as large numbers of neurofibrillary tangles, detected with nickel peroxidase staining, were found in this nucleus in all Alzheimer's disease cases, including those with minimal cell loss.

Quantitative electromyographic changes following modification of central dopaminergic transmission.

Muscle tone was assessed by measurement of quantitative electromyographic (EMG) activity recorded from electrodes chronically implanted in the gastrocnemius and anterior tibialis muscles of conscious, unrestrained rats. Following treatment with reserpine or denervation with 6-hydroxydopamine a significant increase in EMG activity of both muscles was observed, confirming the utility of the method for studying the effects of changes in central dopaminergic transmission on muscle tone.

Expression of stereotyped behaviour requires stimulation of nigral D1 dopamine receptors.

Dopamine receptors in the pars reticulata of the substantia nigra were inactivated following bilateral injections of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Loss of D1, but not D2, receptors was associated with a significant decrease in the incidence of stereotyped head-down sniffing elicited by the mixed D1/D2 receptor agonist, apomorphine. The results support the hypothesis that D1 receptors in the substantia nigra are necessary for the expression of dopamine mediated stereotyped behaviour.

Effects of inactivation of D1 dopamine receptors on stereotypic and thermic responses to quinpirole (LY 171555).

The purpose of the present study was to investigate reports that the expression of dopamine agonist-induced behaviours is dependent upon the ratio of D1 to D2 receptor activation. Selective inactivation of the D1 dopamine receptor was achieved using the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while D2 receptors were maintained at control levels by the use of a D2 antagonist, raclopride. Stereotypic and hypothermic responses to quinpirole (LY 171555) were assessed and related to striatal D1 and D2 receptor concentrations. Results showed that the incidence of stereotyped sniffing behaviour induced by LY 171555 was reduced in parallel with D1 receptor loss and sniffing behaviour was abolished at low D1 receptor (less than 40% of control) concentrations. Hypothermic responses to LY 171555 were unaffected by D1 receptor loss. These findings suggest that activation of D1 receptors is a critical component of stereotypic, but not hypothermic, responses to LY 171555, the magnitude of the sniffing response being positively associated with D1 receptor concentration.

The industrial chemical Tinuvin 123 does not induce dopaminergic neurotoxicity in C57Bl/6 mice.

We have investigated the acute effects of systemic administration of Tinuvin 123 on nigro-striatal dopaminergic neurons in the C57Bl/6 mouse. Tinuvin 123 was administered subcutaneously (s.c.) twice, 16 h apart, at doses of 0, 2, 20 or 200 mg/kg body weight to a total of 48 male C57Bl/6 mice (12 animals/group). Seven days following the last dose the animals were decapitated and the brains removed. No deaths occurred during the study. There were no differences between the mean body weights of any of the experimental groups prior to or following Tinuvin 123 treatment. Animals treated s.c. with 2 mg/kg Tinuvin 123 exhibited no changes in striatal dopamine or metabolite concentrations compared with vehicle-treated animals. Higher doses of Tinuvin 123 (20 and 200 mg/kg) resulted in a moderate loss of striatal dopamine (31 and 38%) but concentrations of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid and the neurotransmitters serotonin, aspartate, gamma aminobutyric acid and glutamate were unchanged. The total number of tyrosine hydroxylase-immunoreactive neurons in the entire substantia nigra were equivalent in the vehicle- and Tinuvin 123-treated animals at all doses, thus no neuronal loss was demonstrated. In conclusion, this study demonstrates no evidence that systemic administered Tinuvin 123 induces dopaminergic neurotoxicity in C57Bl/6 mice.

Arguments for the use of dopamine receptor agonists in clinical and preclinical Parkinson's disease.

On the basis of experimental studies which have demonstrated deleterious effects of L-DOPA (L-3,4-dihydroxyphenylalanine) in vivo and in vitro, it has been suggested that L-DOPA itself may contribute to the progression of Parkinson's disease. This hypothesis is, for many clinicians, the rationale for postponing the employment of and reducing the applied dosage of L-DOPA and for beginning therapy with dopamine receptor agonists or the monoamine oxidase type B (MAO-B) inhibitor selegiline. Furthermore, clinical studies have demonstrated that early treatment with dopamine receptor agonists is associated with a lower incidence of motor fluctuations and dyskinesia. Dopamine receptor agonists exert their symptomatic effect by directly activating dopamine receptors, bypassing the presynaptic synthesis of dopamine and the degenerating nigro-striatal dopaminergic system. They can thus also be of benefit late in the therapy of the disorder. In addition, the pharmacological profile of dopamine receptor agonists suggests a possible neuroprotective effect. This paper reviews briefly the pharmacology of dopamine receptor agonists and basic knowledge concerning the dopamine receptor stimulation which underlies their therapeutic effect. Preclinical approaches for demonstrating neuroprotective effects and their clinical relevance are also discussed.

Impaired iron homeostasis in Parkinson's disease.

Despite physiological systems designed to achieve iron homeostasis, increased concentrations of brain iron have been demonstrated in a range of neurodegenerative diseases. These including the parkinsonian syndromes, the trinucleotide repeat disorders and the dementia syndromes. The increased brain iron is confined to those brain regions most affected by the degeneration characteristic of the particular disorder and is suggested to stimulate cell damage via oxidative mechanisms. Changes in central iron homeostasis have been most closely investigated in PD, as this disorder is well characterised both clinically and pathologically. PD is associated with a significant increase in iron in the degenerating substantia nigra (SN) and is measureable in living PD patients and in post-mortem brain. This increase, however, occurs only in the advanced stages of the disease, suggesting that this phenonoma may be a secondary, rather than a primary initiating event, a hypothesis also supported by evidence from animal experiments. The source of the increased iron is unknown but a variety of changes in iron homeostasis have been identified in PD, both in the brain and in the periphery. The possibility that an increased amount of iron may be transported into the SN is supported by data demonstrating that one form of the iron-binding glycoprotein transferrin family, lactotransferrin, is increased in surviving neurons in the SN in the PD brain and that this change is associated with increased numbers of lactotransferrin receptors on neurons and microvessels in the parkinsonian SN. These changes could represent one mechanism by which iron might concentrate within the PD SN. Alternatively, the measured increased in iron might result from a redistribution of ferritin iron stores. Ferritin is located in glial cells while the degenerating neurons do not stain positive for ferritin. As free radicals are highly reactive, it is unlikely that glial-derived free radicals diffuse across the intracellular space in sufficent quantities to damage neuronal constituents. If intracellular iron release contributes to neuronal damage it seems more probable that an intraneuronal iron source is responsible for oxidant-mediated damage. Such a iron source is neuromelanin (NM), a dark-coloured pigment found in the dopaminergic neurons of the human SN. In the normal brain, NM has the ability to bind a variety of metals, including iron, and increased NM-bound iron is reported in the parkinsonian SN. The consequences of these phenomena for the cell have not yet been clarified. In the absence of significant quantities of iron NM can act as an antioxidant, in that it can interact with and inactivate free radicals. On the other hand, in the presence of iron NM appears to act as a proxidant, increasing the rate of free radical production and thus the oxidative load within the vulnerable neurons. Given that increased iron is only apparent in the advanced stages of the disease it is unlikely that NM is of importance for the primary aetiology of PD. A localised increase in tissue iron and its interaction with NM may be, however, important as a secondary mechanism by increasing the oxidative load on the cell, thereby driving neurodegeneration.

Strategies for the protection of dopaminergic neurons against neurotoxicity.

Degenerative diseases of the central nervous system (CNS) frequently have a predilection for specific cell populations. An explanation for the selective vulnerability of particular neuronal populations and the mechanisms of cell death remains, as yet, elusive. Partial elucidation of the processes underlying the selective action of neurotoxic substances such as iron, 6-hydroxydopamine (6-OHDA), glutamate, kainic acid, quinolinic acid or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has revealed possible molecular mechanisms for neurodegeneration. Hypotheses regarding the neurotoxic mechanisms of these substances have evolved based on our understanding of the pathogenesis of cell death in neurodegenerative disorders and have been the rationale for neuroprotective approaches. Various experimental models have demonstrated that monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists exert a neuroprotective effect at the cellular, neurochemical and functional levels, however as yet it has not been possible to demonstrate an unequivocal neuroprotective effect of these substances in clinical studies. This does not suggest, however, that the pathogenetic processes underlying neurodegenerative disorders are not amenable to neuroprotective treatment. This chapter briefly reviews the mechanisms underlying dopaminergic cell death in Parkinson's disease (PD) as an example of a neurodegenerative disorder and discusses preclinical approaches which attempt to demonstrate the neuroprotective effects of representative drugs in experimental models of this disorder. The problems associated with carrying out clinical neuroprotective studies aimed to demonstrate neuroprotection in PD are also discussed.