Natural killer cells have an activated profile in early Parkinson's disease.

Immune dysregulation is heavily implicated in Parkinson's disease (PD) but the role of Natural Killer (NK) cells has not been well characterised. Accumulating evidence indicates the immune response peaks early in the disease, hence this study focused on characterising NK cells in recently diagnosed PD. PBMCs were obtained from PD cases (< 2 years duration) and age-matched controls and immunophenotyped using flow cytometry. We found an increased proportion and number of NK cells (CD3-CD56+), mature cytotoxic NK cells (CD3-CD16 + CD56dim), and NK cells expressing the activation marker, NKG2D. This implies NK cells are activated in the earliest stages of PD.

Early constipation predicts faster dementia onset in Parkinson's disease.

Constipation is a common but not a universal feature in early PD, suggesting that gut involvement is heterogeneous and may be part of a distinct PD subtype with prognostic implications. We analysed data from the Parkinson's Incidence Cohorts Collaboration, composed of incident community-based cohorts of PD patients assessed longitudinally over 8 years. Constipation was assessed with the MDS-UPDRS constipation item or a comparable categorical scale. Primary PD outcomes of interest were dementia, postural instability and death. PD patients were stratified according to constipation severity at diagnosis: none (n = 313, 67.3%), minor (n = 97, 20.9%) and major (n = 55, 11.8%). Clinical progression to all three outcomes was more rapid in those with more severe constipation at baseline (Kaplan-Meier survival analysis). Cox regression analysis, adjusting for relevant confounders, confirmed a significant relationship between constipation severity and progression to dementia, but not postural instability or death. Early constipation may predict an accelerated progression of neurodegenerative pathology.

Progression of Neuropsychiatric Symptoms over Time in an Incident Parkinson's Disease Cohort (ICICLE-PD).

BACKGROUND: Cross-sectional studies have identified that the prevalence of neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) ranges from 70-89%. However, there are few longitudinal studies determining the impact of NPS on quality of life (QoL) in PD patients and their caregivers. We seek to determine the progression of NPS in early PD. METHODS: Newly diagnosed idiopathic PD cases (n = 212) and age-matched controls (n = 99) were recruited into a longitudinal study. NPS were assessed using the Neuropsychiatric Inventory with Caregiver Distress scale (NPI-D). Further neuropsychological and clinical assessments were completed by participants, with reassessment at 18 and 36 months. Linear mixed-effects modelling determined factors associated with NPI-D and QoL over 36 months. RESULTS: Depression, anxiety, apathy and hallucinations were more frequent in PD than controls at all time points (p < 0.05). Higher motor severity at baseline was associated with worsening NPI-D scores over time (ß = 0.1, p < 0.05), but not cognition. A higher NPI total score was associated with poorer QoL at any time point (ß = 0.3, p < 0.001), but not changed in QoL scores. CONCLUSION: NPS are significantly associated with poorer QoL, even in early PD. Screening for NPS from diagnosis may allow efficient delivery of better support and treatment to patients and their families.

Toll-like receptors and their therapeutic potential in Parkinson's disease and α-synucleinopathies.

Toll-like receptors (TLRs) are pattern recognition receptors which mediate an inflammatory response upon the detection of specific molecular patterns found on foreign organisms and on endogenous damage-related molecules. These receptors play a major role in the activation of microglia, the innate immune cells of the CNS, and are also expressed in peripheral tissues, including blood mononuclear cells and the gut. It is well established that immune activation, in both the brain and periphery, is a feature of Parkinson's disease as well as other α-synucleinopathies. Aggregated forms of α-synuclein can act as ligands for TLRs (particularly TLR2 and TLR4), and hence these receptors may play a critical role in mediating a detrimental immune response to this protein, as well as other inflammatory signals in Parkinson's and related α-synucleinopathies. In this review, the potential role of TLRs in contributing to the progression of these disorders is discussed. Existing evidence comes predominantly from studies in in vitro and in vivo models, as well as analyses of postmortem human brain tissue and pre-clinical studies of TLR inhibitors. This evidence is evaluated in detail, and the potential for therapeutic intervention in α-synucleinopathies through TLR inhibition is discussed.

Abnormalities of age-related T cell senescence in Parkinson's disease.

BACKGROUND: A wealth of evidence implicates both central and peripheral immune changes as contributing to the pathogenesis of Parkinson's disease (PD). It is critical to better understand this aspect of PD given that it is a tractable target for disease-modifying therapy. Age-related changes are known to occur in the immune system (immunosenescence) and might be of particular relevance in PD given that its prevalence rises with increasing age. We therefore sought to investigate this with respect to T cell replicative senescence, a key immune component of human ageing. METHODS: Peripheral blood mononuclear cells were extracted from blood samples from 41 patients with mild PD (Hoehn and Yahr stages 1-2, mean (SD) disease duration 4.3 (1.2) years) and 41 age- and gender-matched controls. Immunophenotyping was performed with flow cytometry using markers of T lymphocyte activation and senescence (CD3, CD4, CD8, HLA-DR, CD38, CD28, CCR7, CD45RA, CD57, CD31). Cytomegalovirus (CMV) serology was measured given its proposed relevance in driving T cell senescence. RESULTS: Markers of replicative senescence in the CD8+ population were strikingly reduced in PD cases versus controls (reduced CD57 expression (p = 0.005), reduced percentage of 'late differentiated' CD57loCD28hi cells (p = 0.007) and 'TEMRA' cells (p = 0.042)), whilst expression of activation markers (CD28) was increased (p = 0.005). This was not driven by differences in CMV seropositivity. No significant changes were observed in the CD4 population. CONCLUSIONS: This study demonstrates for the first time that the peripheral immune profile in PD is distinctly atypical for an older population, with a lack of the CD8+ T cell replicative senescence which characterises normal ageing. This suggests that 'abnormal' immune ageing may contribute to the development of PD, and markers of T cell senescence warrant further investigation as potential biomarkers in this condition.

Review: The spectrum of clinical features seen with alpha synuclein pathology.

It has been recognized for many years that a number of chronic neurodegenerative diseases of the CNS are characterized by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterized by this type of pathology--namely Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore at around this time, this same protein was also found within the glial inclusion bodies of patients dying with multiple system atrophy (MSA). These three disorders constitute the majority of patients with an 'alpha synucleinopathy', although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's disease (GD). In this review, we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD), as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology.

Putative cortical dopamine levels affect cortical recruitment during planning.

Planning, the decomposition of an ultimate goal into a number of sub-goals is critically dependent upon fronto-striatal dopamine (DA) levels. Here, we examined the extent to which the val158met polymorphism in the catechol O-methyltransferase (COMT) gene, which is thought to primarily alter cortical DA levels, affects performance and fronto-parietal activity during a planning task (Tower of London). COMT genotype was found to modulate activity in the left superior posterior parietal cortex (SPC) during planning, relative to subtracting, trials. Specifically, left SPC blood oxygenation level-dependent (BOLD) response was reduced in groups with putatively low or high cortical DA levels (COMT homozygotes) relative to those with intermediate cortical DA levels (COMT heterozygotes). These set of results are argued to occur either due to differences in neuronal processing in planning (and perhaps subtracting) caused by the COMT genotype and/or the cognitively heterogeneous nature of the TOL, which allows different cognitive strategies to be used whilst producing indistinguishable behavioural performance in healthy adults. The implications of this result for our understanding of COMT's effect on cognition in health and disease are discussed.

Prefrontal dopamine levels determine the balance between cognitive stability and flexibility.

A key mechanism by which the prefrontal cortex (PFC) supports goal-oriented behaviors is attentional set formation: the formation and maintenance of an attentional bias toward relevant features. It has previously been proposed that a common single nucleotide polymorphism (val158met) in the gene that codes for the catechol O-methyltransferase (COMT) enzyme may affect an individual's ability to form and maintain an attentional set by modulating PFC dopamine (DA) levels. Here, we present data from a functional magnetic resonance imaging study that investigated the effect of this polymorphism on the tendency for older adults to display set-like behavior, and we compare these results to preexisting data from Parkinson's Disease (PD) patients. Our results demonstrate that putatively different levels of PFC DA predict both attentional set formation and right dorsolateral PFC (DLPFC) activation. More specifically, while for PD patients, val homozygotes showed heightened DLPFC activation and increased set-like behavior, for healthy older adults, the opposite pattern of results was observed. This interaction between COMT genotype and PD accords well with previous studies that have shown an excess of DA in the PFC in early PD patients and, furthermore, supports the hypothesis that there is an inverted-U shaped functional relationship between PFC DA levels and attentional set formation.

The val158met COMT polymorphism's effect on atrophy in healthy aging and Parkinson's disease.

We investigated whether the val(158)met functional polymorphism of catechol-o-methyltransferase influenced age-related changes in grey matter density and volume, both in healthy individuals (n=80, ages 18-79) and those with Parkinson's disease (n=50). Global grey matter volumes and voxelwise estimates of grey matter volume and density were determined from structural magnetic resonance images at 3T. Male and female ValVal homozygotes (low prefrontal cortical dopamine) had more grey matter in early adulthood, but this difference disappeared with increasing age. The insula and ventral prefrontal cortex had higher grey matter volume in younger, but not older, ValVal homozygotes. Conversely, the dominant premotor cortex revealed genotypic differences in grey matter density in later life. There were no global or local interactions between Parkinson's disease and COMT val(158)met genotype on morphometry. Since the val(158)met polymorphism is associated with differences in cortical dopamine metabolism, our data suggest a role for dopamine in cortical development followed by differential vulnerability to cortical atrophy across the adult life span.

BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson's disease.

BACKGROUND: Levodopa induced dyskinesias (LID) are a common problem which ultimately limit the effective treatment of patients with Parkinson's disease (PD). There is accumulating evidence that LID develop due to abnormal synaptic plasticity, which is in turn influenced by the release of brain derived neurotrophic factor (BDNF). METHODS: The influence of a common functional polymorphism of the BDNF gene on the risk of developing dyskinesias in a large cohort of patients with PD (n = 315), who were independently and variably treated with levodopa and/or other dopaminergic treatments, was investigated. RESULTS: Patients with the met allele of BDNF, associated with lower activity dependent secretion of BDNF, were at significantly higher risk of developing dyskinesias earlier in the course of treatment with dopaminergic agents (hazard ratio for each additional met allele 2.12, p = 0.001), which persisted following adjustment for potential confounding variables. CONCLUSION: This functional polymorphism may help predict which individuals are most at risk of LID and is consistent with the known actions of BDNF on synaptic plasticity in the striatum.

Parkinson's disease and dopaminergic therapy--differential effects on movement, reward and cognition.

Cognitive deficits are very common in Parkinson's disease particularly for 'executive functions' associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative 'on' and 'off' states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1-4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico-striato-thalamo-cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease.

Evolution of cognitive dysfunction in an incident Parkinson's disease cohort.

We have previously performed detailed clinical and neuropsychological assessments in a community-based cohort of patients with newly diagnosed parkinsonism, and through analysis of a subcohort with idiopathic Parkinson's disease (PD), we have demonstrated that cognitive dysfunction occurs even at the time of PD diagnosis and is heterogeneous. Longitudinal follow-up of the cohort has now been performed to examine the evolution of cognitive dysfunction within the early years of the disease. One hundred and eighty (79%) eligible patients from the original cohort with parkinsonism were available for re-assessment at between 3 and 5 years from their initial baseline assessments. PD diagnoses were re-validated with repeated application of the UKPDS Brain Bank criteria in order to maximize sensitivity and specificity, following which a diagnosis of idiopathic PD was confirmed in 126 patients. Thirteen out of 126 (10%) had developed dementia at a mean (SD) of 3.5 (0.7) years from diagnosis, corresponding to an annual dementia incidence of 30.0 (16.4-52.9) per 1000 person-years. A further 57% of PD patients showed evidence of cognitive impairment, with frontostriatal deficits being most common amongst the non-demented group. However, the most important clinical predictors of global cognitive decline following correction for age were neuropsychological tasks with a more posterior cortical basis, including semantic fluency and ability to copy an intersecting pentagons figure, as well as a non-tremor dominant motor phenotype at the baseline assessment. This work clarifies the profile of cognitive dysfunction in early PD and demonstrates that the dementing process in this illness is heralded by both postural and gait dysfunction and cognitive deficits with a posterior cortical basis, reflecting probable non-dopaminergic cortical Lewy body pathology. Furthermore, given that these predictors of dementia are readily measurable within just a few minutes in a clinical setting, our work may ultimately have practical implications in terms of guiding prognosis in individual patients.

Investigation of TGFB2 as a candidate gene in multiple sclerosis and Parkinson's disease.

Given the known roles of TGFbeta2 in both regulating the immune system and promoting the survival of dopaminergic neurons, it is feasible that genetic variations in TGFB2 might play an aetiological role in neurological diseases such as Multiple Sclerosis (MS) and Parkinson's disease (PD). Hence we performed an indirect association analysis of TGFB2 using 8 haplotype-tagging SNPs in a population of 937 MS patients, 538 PD cases and 2022 controls. We found no evidence for association with susceptibility or progression of MS, but have demonstrated a trend towards association of the 5' region of the gene with susceptibility to PD. Further analysis of TGFB2 is warranted in other PD cohorts.

Prevalence of the LRRK2 G2019S mutation in a UK community based idiopathic Parkinson's disease cohort.

The LRRK2 G2019S mutation is the commonest genetic cause of Parkinson's disease (PD) identified to date, although estimates of its prevalence in idiopathic disease vary considerably. Our objectives were to determine G2019S mutation frequency in an unselected, community based cohort of idiopathic PD cases from the UK and to describe phenotypic characteristics among carriers. The mutation was present in two of 519 cases (0.4%) and none of 887 control individuals. The true prevalence of the mutation in idiopathic disease, its penetrance, and the phenotypic heterogeneity of associated cases have important implications for genetic screening in the clinical field.

Saccadic latency distributions in Parkinson's disease and the effects of L-dopa.

Parkinson's disease (PD) is associated with a loss of central dopaminergic pathways in the brain leading to an abnormality of movement, including saccades. In PD, analysis of saccadic latency distributions, rather than mean latencies, can provide much more information about how the neural decision process that precedes movement is affected by disease or medication. Subject to the constraints of intersubject variation and reproducibility, latency distribution may represent an attractive potential biomarker of PD. Here we report two studies that provide information about these parameters, and demonstrate a novel effect of dopamine on saccadic latency, implying that it influences the neural decision process itself. We performed a detailed cross-sectional study of saccadic latency distributions during a simple step task in 22 medicated patients and 27 age-matched controls. This revealed high intersubject variability and an overlap of PD and control distributions. A second study was undertaken on a different population specifically to investigate the effects of dopamine on saccadic latency distributions in 15 PD patients. L-dopa was found to prolong latency, although the magnitude of the effect varied between subjects. The implications of these observations for the use of saccadic latency distributions as a potential biomarker of PD are discussed, as are the effects of L-dopa on neural decision making, where it is postulated to increase the criterion level of evidence required before the decision to move is made.