Abstract Background Patients with Parkinson's disease (PD) frequently have gastrointestinal symptoms (e.g. constipation) and exhibit the PD-typical pathohistology in the enteric nervous system (ENS). Both, clinical symptoms and pathohistological changes in the ENS occur at early stages and can precede the motor manifestations of PD. Two recent studies reported an association between changes in gut microbiota composition and PD. We hypothesized that alterations in gut microbiota might be accompanied by altered concentrations of short chain fatty acids (SCFA), one main metabolic product of gut bacteria. Methods We quantitatively analyzed SCFA concentrations (using gas chromatography) and microbiota composition (using quantitative PCR) in fecal samples of 34 PD patients and 34 age-matched controls. Results Fecal SCFA concentrations were significantly reduced in PD patients compared to controls. The bacterial phylum Bacteroidetes and the bacterial family Prevotellaceae were reduced, Enterobacteriaceae were more abundant in fecal samples from PD patients compared to matched controls. Conclusions Our study confirms the recently reported association between PD and the abundance of certain gut microbiota and shows a reduction in fecal SCFA concentrations (one main metabolic product of certain gut bacteria). The reduction in SCFA might, theoretically, induce alterations in the ENS and contribute to gastrointestinal dysmotility in PD. Prospective longitudinal studies in subjects at risk for PD are required to further elucidate the causal role of gut microbiota and microbial products in the development of PD and PD-associated dysmotility.
Abstract Background Remote, non-invasive and objective tests that can be used to support expert diagnosis for Parkinson's disease (PD) are lacking. Methods Participants underwent baseline in-clinic assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS), and were provided smartphones with an Android operating system that contained a smartphone application that assessed voice, posture, gait, finger tapping, and response time. Participants then took the smart phones home to perform the five tasks four times a day for a month. Once a week participants had a remote (telemedicine) visit with a Parkinson disease specialist in which a modified (excluding assessments of rigidity and balance) UPDRS performed. Using statistical analyses of the five tasks recorded using the smartphone from 10 individuals with PD and 10 controls, we sought to: (1) discriminate whether the participant had PD and (2) predict the modified motor portion of the UPDRS. Results Twenty participants performed an average of 2.7 tests per day (68.9% adherence) for the study duration (average of 34.4 days) in a home and community setting. The analyses of the five tasks differed between those with Parkinson disease and those without. In discriminating participants with PD from controls, the mean sensitivity was 96.2% (SD 2%) and mean specificity was 96.9% (SD 1.9%). The mean error in predicting the modified motor component of the UPDRS (range 11–34) was 1.26 UPDRS points (SD 0.16). Conclusion Measuring PD symptoms via a smartphone is feasible and has potential value as a diagnostic support tool.
Abstract Background Identifying factors influencing phenotypic heterogeneity in Parkinson's Disease is crucial for understanding variability in disease severity and progression. Age and gender are two most basic epidemiological characteristics, yet their effect on expression of PD symptoms is not fully defined. We aimed to delineate effects of age and gender on the phenotype in an incident cohort of PD patients and healthy controls from the Oxford Parkinson Disease Centre (OPDC). Methods Clinical features, including demographic and medical characteristics and non-motor and motor symptoms, were analyzed in a group of PD patients within 3 years of diagnosis and a group of healthy controls from the OPDC cohort. Disease features were stratified according to age and compared between genders, controlling for effects of common covariates. Results 490 PD patients and 176 healthy controls were analyzed. Stratification by age showed increased disease severity with age on motor scales. Some non-motor features showed similar trend, including cognition and autonomic features. Comparison across genders highlighted a pattern of increased severity and greater symptom symmetricality in the face, neck and arms in men with women having more postural problems. Amongst the non-motor symptoms, men had more cognitive impairment, greater rate of REM behavior disorder (RBD), more orthostatic hypotension and sexual dysfunction. Conclusions Age in PD is a strong factor contributing to disease severity even after controlling for the effect of disease duration. Gender-related motor phenotype can be defined by a vertical split into more symmetrical upper-body disease in men and disease dominated by postural symptoms in women.
Abstract Background Freezing of gait is a common cause of disability and falls in patients with Parkinson's disease. We studied brain functional connectivity, by means of resting-state functional magnetic resonance imaging, in patients with Parkinson's disease and freezing of gait. Methods Resting-state functional magnetic resonance imaging at 3 T was collected in 29 patients with Parkinson's disease, of whom 16 presented with freezing of gait as determined by a validated freezing of gait questionnaire, and 15 matched healthy controls. Single-subject and group-level independent component analysis was used to identify the main resting-state networks differing between Parkinson's disease patients with and without freezing of gait. Statistical analysis was performed using BrainVoyager QX. Results Between-group differences in resting-state networks revealed that patients with freezing of gait exhibit significantly reduced functional connectivity within both “executive-attention” (in the right middle frontal gyrus and in the angular gyrus) and visual networks (in the right occipito-temporal gyrus) [ p < 0.05 corrected for multiple comparisons]. Freezing of gait clinical severity was significantly correlated with decreased connectivity within the two networks. Consistent with their “executive-attention” network impairment, patients with freezing of gait scored lower on tests of frontal lobe functions (phonemic verbal fluency: p = 0.005; frontal assessment battery: p < 0.001; ten point clock test: p = 0.04). Conclusions Our findings suggest that a resting-state functional connectivity disruption of “executive-attention” and visual neural networks may be associated with the development of freezing of gait in patients with Parkinson's disease.
Abstract Introduction Intermittent oral delivery of levodopa is a major contributing factor for motor complications in Parkinson's disease (PD). Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) into the jejunum using a portable pump via percutaneous endoscopic gastrostomy (PEG) improves motor complications and quality of life (QoL). Objectives To record long-term effectiveness of advanced PD patients undergoing LCIG infusion in routine care, by Unified Parkinson's Disease Rating Scale (UPDRS), Non-Motor Symptoms Scale (NMSS), PDQ-8 and EQ-5D questionnaires. Methods Overall, 375 patients from 75 movement disorder centers in 18 countries were enrolled in this prospective non-interventional study. The 12-month interim outcomes of the first 172 included patients are presented here. Results There were reductions of mean daily “Off” time from baseline (BL) (7.1 ± 3.5 h) and “On” time with dyskinesias (5.2 ± 4.5 h) at month 12 (M12) of −4.7 ± 3.4 and −1.7 ± 5.0 h respectively (p < 0.0001; p = 0.0228). UPDRS II and III “On” scores decreased from BL to M12 (p = 0.0107 and p = 0.0128). Total NMSS and PDQ-8 scores improved at M12 (p = 0.0014 and p = 0.0100). Mean LCIG dose administered through PEG at first visit (day after implantation) was 1304 ± 618 mg/day and remained stable through M12. Continuous LCIG infusion tolerability and adverse drug reactions were consistent with the known safety profile of previous studies. Conclusions This observational, routine-care study supports long-term safety and efficacy of LCIG infusion in advanced PD including motor, non-motor and QoL improvements.
Abstract Background The relative impact of motor- and non-motor symptoms on health-related quality of life in early Parkinson's disease is poorly documented. Methods 188 patients with incident Parkinson's disease from a population-based study were examined at the time of diagnosis, before initiation of dopaminergic treatment, with follow-up of 166 patients three years later. Health-related quality of life was assessed by the 36-item Short-form Health Survey (SF-36). Motor and non-motor variables were derived from the Unified Parkinson's disease rating scale and other established scales. Results Multiple regression analyses showed that the non-motor symptoms strongest associated with reduced SF-36 scores at diagnosis and three years later were depression, fatigue and sensory complaints. The motor symptoms most related to impaired SF-36 scores were problems with gait and activities of daily living that cover personal needs. The variance of SF-36 mental summary scores was much better explained by non-motor vs. motor symptoms, both at baseline ( R2 = 0.384 vs. 0.095) and 3 years later ( R2 = 0.441 vs. 0.195). Also SF-36 physical summary scores were better explained by non-motor vs. motor symptoms with R2 = 0.372 vs. 0.322 at baseline and R2 = 0.468 vs. 0.315 after 3 years. Conclusion In early PD, including the phase before dopaminergic treatment is initiated, non-motor symptoms are more important for reduced health-related quality of life than motor symptoms. Fatigue, depression, sensory complaints and gait disturbances emerge as the most relevant symptoms and should be given corresponding attention in the management of patients with early PD.
Abstract Introduction Movement disorder specialists can achieve a high level of accuracy when clinically diagnosing parkinsonism syndromes. However, data about the diagnostic accuracy among general neurologists is limited. Objectives This study investigated the recent diagnostic accuracy of parkinsonism syndromes by general neurologists. Methods A retrospective examination of 1362 post-mortem cases diagnosed in the years 2000–2012 by neuropathologists was performed. Out of these cases, we identified 111 patients who received a clinical parkinsonism diagnosis during life and 122 patients who received a neuropathological diagnosis of a parkinsonism syndrome post-mortem including 11 incidental cases. Results Fifty-eight (75.3%) of the 77 patients who had received clinical Parkinson's disease (PD) diagnoses were confirmed after the neuropathological examination. The sensitivity of the clinical diagnosis for idiopathic Parkinson's disease (PD) was 89.2% and the specificity was 57.8%. The corresponding numbers for progressive supranuclear palsy (PSP) were 52.9% and 100%, and for multiple system atrophy (MSA) were 64.3% and 99.0%, respectively. Conclusions Parkinson's disease is heavily overdiagnosed by general neurologists, whereas parkinsonism plus syndromes are underdiagnosed. Despite improvements in the diagnostic methods during recent decades and the development of diagnostic clinical criteria for parkinsonian syndromes, the diagnostic accuracy of Parkinson's disease remains relatively low, and 1/4 of diagnoses are incorrect.
Abstract Background Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson's disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. Methods Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50–75, on medication ≥6 months but ≤4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) ( n = 15) or DBS + ODT ( n = 15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. Results As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. Medication requirements in the DBS + ODT group were lower at all time points with a maximal difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS + ODT group suffered serious adverse events; remaining adverse events were mild or transient. Conclusions This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD.
Objectives: Differential diagnosis of Parkinson's disease (PD) and other neurodegenerative parkinsonism by clinical consensus criteria and diagnostic imaging is often difficult. I-123-meta-iodobenzylguanidine (I-123-MIBG) myocardial scintigraphy is a useful imaging tool for differentiating PD from other parkinsonism. The purpose of the present study is to systematically review and perform a meta-analysis of studies on the diagnostic performance of I-123-MIBG myocardial scintigraphy for the differential diagnosis of PD and other neurodegenerative parkinsonism, specifically multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Methods: A computer literature search of the PubMED/MEDLINE database was conducted to find relevant published articles on I-123-MIBG myocardial scintigraphy for the differential diagnosis of PD and other neurodegenerative parkinsonism. We used the bivariate random-effects model to obtain the pooled estimates of the sensitivity and specificity and the corresponding 95% confidence intervals. Results: Thirteen studies comprising 845 patients including 625 PD and 220 other neurodegenerative parkinsonism were analyzed. The pooled sensitivity and specificity to differentiate PD from other neurodegenerative parkinsonism by the early heart-to-mediastinum (H/M) ratio were 82.6% and 89.2%, respectively, and those by the delayed H/M ratio were 89.7% and 82.6%, respectively. When PD was limited to early stage (Hoehn-Yahr stage 1 or 2), the pooled sensitivity and specificity by the delayed H/M ratio were 94.1% and 80.2%, respectively. Conclusions: The present meta-analysis confirmed high sensitivity and specificity of I-123-MIBG myocardial scintigraphy for differentiating PD from other neurodegenerative parkinsonism in both early and delayed imaging phases. Furthermore, I-123-MIBG myocardial scintigraphy was highly effective for distinguishing early PD. (c) 2012 Elsevier Ltd. All rights reserved.
This registry evaluated the 24-month safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) treatment in advanced Parkinson's disease (PD) patients under routine clinical care. Motor fluctuations, dyskinesia, non-motor symptoms, quality of life, and safety were evaluated. Observations were fully prospective for treatment-naïve patients (60% of patients) and partially retrospective for patients with ≤12 months of pre-treatment with LCIG (40% of patients). Hours of “On” and “Off” time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale part IV items 32 and 39. Overall, 375 patients were enrolled by 75 movement disorder centers in 18 countries and 258 patients completed the registry. At 24 months LCIG treatment led to significant reductions from baseline in “Off” time (hours/day) (mean ± SD = −4.1 ± 3.5, < 0.001), “On” time with dyskinesia (hours/day) (−1.1 ± 4.8, = 0.006), Non-Motor Symptom Scale total (−16.7 ± 43.2, < 0.001) and individual domains scores, and Parkinson's Disease Questionnaire-8 item total score (−7.1 ± 21.0, P < 0.001). Adverse events deemed to have a possible/probable causal relationship to treatment drug/device were reported in 194 (54%) patients; the most frequently reported were decreased weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device issues (4.8%), and polyneuropathy (4.5%). LCIG treatment led to sustained improvements in motor fluctuations, non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal domains, as well as quality of life in advanced PD patients over 24 months. Safety events were consistent with the established safety profile of LCIG.
Abstract Previous data on the prevalence of olfactory dysfunction in Parkinson's disease (PD) range from 45% to 90%. The present multicenter study aimed to provide data on the prevalence of smell loss in a large sample of PD patients from three independent populations. Olfactory sensitivity was tested in 400 patients from Australia, Germany, and The Netherlands by means of a psychophysical olfactory test, the “Sniffin' Sticks”, which is comprised of 3 subtests of olfactory function. Out of the total number of patients 45.0% presented as functionally anosmic, 51.7% were hyposmic, whereas only 3.3% were normosmic. This indicates that 96.7% of PD patients present with significant olfactory loss when compared to young normosmic subjects. This figure falls to 74.5%, however, when adjusted to age-related norms. Thus, olfactory dysfunction should be considered as a reliable marker of the disease.
Abstract Background and objective Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer's disease. The aim of this work was to determine whether the differences of serum miRNAs profiling could distinguish PD patients from healthy individuals. Methods We collected serum samples from 106 sporadic PD patients and 91 age/gender-matched healthy controls. Serum miRNAs were analysed by Solexa sequencing followed by a qRT-PCR examination. The qRT-PCR assay, which was divided into two phases, was used to validate the expression of miRNAs screened by Solexa sequencing. Receiver operating characteristic (ROC) curve analysis and clustering analysis were performed to determine the diagnostic usefulness of the selected miRNAs for PD. Results In this study, we generated a profile of 5 serum miRNAs: miR-195 was up-regulated, and miR-185, miR-15b, miR-221 and miR-181a were down-regulated. Conclusion This group of five miRNAs can precisely distinguish PD patients from health individuals and may be used as a potential serum-based biomarker for the diagnosis of PD.
Abstract Background Recent studies reported a high prevalence of small intestinal bacterial overgrowth (SIBO) in Parkinson's disease (PD), and a possible association with gastrointestinal symptoms and worse motor function. We aimed to study the prevalence and the potential impact of SIBO on gastrointestinal symptoms, motor function, and quality of life in a large cohort of PD patients. Methods 103 Consecutive PD patients were assessed using the lactulose-hydrogen breath test; questionnaires of gastrointestinal symptoms and quality of life (PDQ-39); the Unified PD Rating Scale (UPDRS) including “on”-medication Part III (motor severity) score; and objective and quantitative measures of bradykinesia (Purdue Pegboard and timed test of gait). Patients and evaluating investigators were blind to SIBO status. Results 25.3% of PD patients were SIBO-positive. SIBO-positive patients had a shorter mean duration of PD (5.2 ± 4.1 vs. 8.1 ± 5.5 years, P = 0.007). After adjusting for disease duration, SIBO was significantly associated with lower constipation and tenesmus severity scores, but worse scores across a range of “on”-medication motor assessments (accounting for 4.2–9.0% of the variance in motor scores). There was no association between SIBO and motor fluctuations or PDQ-39 Summary Index scores. Conclusions This is the largest study to date on SIBO in PD. SIBO was detected in one quarter of patients, including patients recently diagnosed with the disease. SIBO was not associated with worse gastrointestinal symptoms, but independently predicted worse motor function. Properly designed treatment trials are needed to confirm a causal link between SIBO and worse motor function in PD.
Abstract Background Deep Brain Stimulation of the Subthalamic Nucleus (STN-DBS) is an effective treatment for Parkinson's disease (PD), but only few studies investigated its long-term efficacy. Furthermore, little is known about the role of PD-subtype on STN-DBS long-term outcome. Objective To report the results of a long-term follow-up (mean 11 years, range 10–13) on 26 patients bilaterally implanted in two centres. Methods Patients were assessed preoperatively and 1, 5 and 11 years after the implant by the Unified Parkinson's Disease Rating Scale (UPDRS) and a battery of neuropsychological tests. Stimulation parameters, drugs dosages, non-motor symptoms and adverse events were also recorded. Results At 11 years, stimulation significantly improved the motor symptoms by 35.8%, as compared to the preoperative off-state. Motor complications were well controlled, with a 84.6% improvement of dyskinesias and a 65.8% improvement of motor fluctuations. Despite this, the UPDRS-II-on score worsened by 88.5%, mainly for the worsening of poorly levodopa-responsive symptoms. More than 70% of the patients performed in the normal range in most of the neuropsychological tests, despite the development of dementia in 22.7%. Age at disease onset, axial subscore in off-condition and presence of REM behaviour disorder at baseline were found to be associated with a higher risk of developing disability over time. Conclusions Our study confirms the long-term safety and efficacy of STN-DBS in PD. Nevertheless, the functionality of patients worsens over time, mainly for the onset and progression of levodopa-resistant and non-motor symptoms. The role of PD-subtype seems to be relevant in the long-term outcome.
Abstract Introduction In PD, Mild Cognitive Impairment (PD-MCI) occurs since early stages of disease. The aims were to assess presence of PD-MCI in untreated, drug-naive PD patients, and to follow-up the sample over 4 years to ascertain evolution of neurocognitive profile. Methods Seventy-six patients underwent neuropsychological testing at baseline (T0), and after 2 (T1:n = 62) and 4 years (T2:n = 55). Diagnosis of PD-MCI and PD-associated dementia (PDD) was made according to current consensus criteria. Results PD-MCI occurred in 25/76 patients (32.9%) at baseline, and 4 of them reverted from PD-MCI to Normal Cognition (Reverters), 7 remained stable (Non-Reverters) and 2 developed PDD at T2; 12 patients were lost to the follow-up. Among the 51 patients with normal cognition (PD-CN) at T0, 27 had normal cognition at T2 (5 of them were Reverters with respect to diagnosis at T1), 5 had MCI at T1 and T2 (Non-Reverters), 9 had MCI at T2 only, whereas 1 developed PDD; 9 patients were lost to the follow-up. At baseline, Reverters (n = 9) had younger age at onset and better performance on constructional visuospatial task than Non-Reverters (n = 12). Compared to patients without PD-MCI at all evaluations (n = 19), Reverters had poorer performance on verbal immediate recall and attention tasks and higher level of apathy at T0. Reduced performance on the Stroop Test at baseline predicted PD-MCI at T2. Conclusion Executive dysfunctions predicted development of PD-MCI after few years from onset. Reversal from PD-MCI to PD-CN was related to young age at onset and high level of apathy at baseline evaluation.
Abstract Autonomic and somatic denervation is well established in Parkinson's disease (PD). Objectives (1) To determine whether corneal confocal microscopy (CCM) can non-invasively demonstrate small nerve fiber damage in PD. (2) To identify relationships between corneal nerve parameters, intraepidermal nerve fiber density (IENFD) and clinical features of PD. Methods Twenty-six PD patients and 26 controls underwent CCM of both eyes. 24/26 PD patients and 10/26 controls underwent skin biopsies from the dorsa of both feet. PD patients underwent assessment of parasympathetic function [deep breathing heart rate variability (DB-HRV)], autonomic symptoms [scale for outcomes in Parkinson's disease – autonomic symptoms (SCOPA-AUT)], motor symptoms [UPDRS-III “ON”] and cumulative Levodopa dose. Results PD patients had significantly reduced corneal nerve fiber density (CNFD) with increased corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) compared to controls. CNBD and CNFL but not CNFD correlated inversely with UPDRS-III and SCOPA-AUT. All CCM parameters correlated strongly with DB-HRV. There was no correlation between CCM parameters and disease duration, cumulative Levodopa dose or pain. IENFD was significantly reduced in PD compared to controls and correlated with CNFD and UPDRS-III. However, unlike CCM measures, IENFD correlated with disease duration and cumulative Levodopa dose but not with autonomic dysfunction. Conclusion CCM identifies corneal nerve fiber pathology, which correlates with autonomic symptoms, parasympathetic deficits and motor scores in patients with PD. IENFD is also reduced and correlates with CNFD and motor symptoms but not parasympathetic deficits, indicating it detects different aspects of peripheral nerve pathology in PD.
Abstract Introduction Parkinson's disease dementia (PDD) is associated with poorer quality of life (QoL). Prior to the onset of PDD, many patients experience progressive cognitive impairment. There is a paucity of longitudinal studies investigating the effects of cognitive decline on QoL. This study aimed to determine the longitudinal impact of cognitive change on QoL in an incident PD cohort. Methods Recently diagnosed patients with PD (n = 212) completed a schedule of neuropsychological assessments and QoL measures; these were repeated after 18 (n = 190) and 36 months (n = 158). Mild cognitive impairment (PD-MCI) was classified with reference to the Movement Disorder Society criteria. Principal component analysis was used to reduce 10 neuropsychological tests to three cognitive factors: attention, memory/executive function, and global cognition. Results Baseline PD-MCI was a significant contributor to QoL (β = 0.2, p < 0.01). For those subjects (9%) who developed dementia, cognitive function had a much greater impact on QoL (β = 10.3, p < 0.05). Multivariate modelling showed attentional deficits had the strongest predictive power (β = −2.3, p < 0.01); brief global tests only modestly predicted decline in QoL (β = −0.4, p < 0.01). Conclusions PD-MCI was associated with poorer QoL over three years follow up. Cognitive impairment had a greater impact on QoL in individuals who developed dementia over follow-up. Impaired attention was a significant determinant of QoL in PD. Interventions which improve concentration and attention in those with PD could potentially improve QoL.
Abstract Background Reactive microgliosis, hallmark of neuroinflammation, may contribute to neuronal degeneration, as shown in several neurodegenerative diseases. We in vivo evaluated microglia activation in early dementia with Lewy bodies, still not reported, and compared with early Parkinson's disease, to assess possible differential pathological patterns. Methods We measured the [11 C]-PK11195 binding potentials with Positron Emission Tomography, using a simplified reference tissue model, as marker of microglia activation, and cerebral spinal fluid protein carbonylation levels, as marker of oxidative stress. Six dementia with Lewy bodies and 6 Parkinson's disease patients within a year from the onset, and eleven healthy controls were included. Clinical diagnosis was confirmed at a 4-year follow-up. Results In dementia with Lewy bodies as well as in Parkinson's disease, we found significant ( p < 0.001) [11 C]-PK11195 binding potential increases in the substantia nigra and putamen. Patients with Lewy bodies dementia had extensive additional microglia activation in several associative cortices. This was evident also at a single subject level. Significant increase of Cerebral Spinal Fluid protein carbonylation was shown in both patients' groups. Conclusions [11 C]-PK11195 Positron Emission Tomography imaging revealed neuroinflammation in dementia with Lewy bodies and Parkinson's disease, mirroring, even at a single subject level, the common and the different topographical distribution of neuropathological changes, yet in the earliest stages of the disease process. Focusing on those events that characterize parkinsonisms and Parkinson's disease may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection.
Adenosine derived from the degradation of ATP/AMP functions as a signalling molecule in the nervous system through the occupation of A1, A2, and A3 adenosine receptors. Adenosine A(2A) receptors have a selective localization to the basal ganglia and specifically to the indirect output pathway, and as a consequence offer a unique opportunity to modulate the output from the striatum that is believed critical to the occurrence of motor components of PD. Indeed, the ability of A(2A) antagonists to modulate basal ganglia neurotransmission has been shown to be associated with improved motor function in experimental models of PD. This suggests that A(2A) antagonists would be effective as a symptomatic treatment in humans without provoking marked dyskinesia. Indeed, the A(2A) antagonist istradefylline reduces OFF time in moderate- to late-stage patients with PD already receiving dopaminergic therapy, with an increase in non-troublesome dyskinesia. Adenosine and adenosine receptors also exert actions relevant to pathogenesis in PD, raising the possibility of their use as neuroprotective agents. Both epidemiologic evidence and the current preclinical data strongly support a role for A(2A) antagonists in protecting dopaminergic neurons and influencing the onset and progression of PD. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.
Abstract Neuropsychological (mostly posterior-cortical) deficits, quantitative magnetic resonance imaging (MRI) atrophy patterns, and low cerebrospinal fluid (CSF) levels of amyloid-β have been separately related to worsening cognition in Parkinson's disease (PD). However, these biomarkers have not been longitudinally assessed in combination as PD-dementia predictors. In this prospective longitudinal study, 27 non-demented PD patients underwent CSF, neuropsychological and 3-T brain-MRI studies at baseline and were re-assessed 18 months later in terms of progression to dementia (primary outcome) and longitudinal neuropsychological and cortical thickness changes (secondary outcomes). At follow-up 11 patients (41%) had progressed to dementia. Lower CSF amyloid-β, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions were significant baseline dementia predictors in binary logistic regressions as quantitative and/or dichotomised traits. All participants without baseline biomarker abnormalities remained non-demented whereas all with abnormalities in each biomarker type progressed to dementia, with intermediate risk for those showing abnormalities in a single to two biomarker types ( p = 0.006). Both the dementia-outcome and low baseline CSF amyloid-β were prospectively associated with limbic and posterior-cortical neuropsychological decline and frontal, limbic and posterior-cortical thinning from baseline to follow-up. These findings suggest that the combination of CSF amyloid-β, neuropsychological and cortical thickness biomarkers might provide a basis for dementia-risk stratification and progression monitoring in PD.