Early Phase Of Parkinson's Disease Research Articles

Positive relation between dopamine neuron degeneration and metabolic connectivity disruption in the MPTP plus probenecid mouse model of Parkinson's disease

The clinical manifestation of Parkinson's disease (PD) appears when neurodegeneration is already advanced, compromising the efficacy of disease-modifying treatment approaches. Biomarkers to identify the early stages of PD are therefore of paramount importance for the advancement of the therapy of PD. In the present study, by using a mouse model of PD obtained by subchronic treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the clearance inhibitor probenecid (MPTPp), we identified prodromal markers of PD by combining in vivo positron emission tomography (PET) imaging and ex vivo immunohistochemistry. Longitudinal PET imaging of the dopamine transporter (DAT) by [18F]-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane ([18F]-FP-CIT), and brain glucose metabolism by 2-deoxy-2-[18F]-fluoroglucose ([18F]-FDG) were performed before MPTPp treatment and after 1, 3, and 10 MPTPp administrations, in order to assess relation between dopamine neuron integrity and brain connectivity. The results show that in vivo [18F]-FP-CIT in the dorsal striatum was not modified after the first administration of MPTPp, tended to decrease after 3 administrations, and significantly decreased after 10 MPTPp administrations. Post-mortem immunohistochemical analyses of DAT and tyrosine hydroxylase (TH) in the striatum showed a positive correlation with [18F]-FP-CIT, confirming the validity of repeated MPTPp-treated mice as a model that can reproduce the progressive pathological changes in the early phases of PD. Analysis of [18F]-FDG uptake in several brain areas connected to the striatum showed that metabolic connectivity was progressively disrupted, starting from the first MPTPp administration, and that significant connections between cortical and subcortical regions were lost after 10 MPTPp administrations, suggesting an association between dopamine neuron degeneration and connectivity disruption in this PD model. The results of this study provide a relevant model, where new drugs that can alleviate neurodegeneration in PD could be evaluated preclinically.

Neuroimaging Techniques in Differentiating Parkinson's Disease from Drug-Induced Parkinsonism: A Comprehensive Review.

Neuroimaging can provide significant benefits in evaluating patients with movement disorders associated with drugs. This literature review describes neuroimaging techniques performed to distinguish Parkinson's disease from drug-induced parkinsonism. The dopaminergic radiotracers already reported to assess patients with drug-induced parkinsonism are [123I]-FP-CIT, [123I]-β-CIT, [99mTc]-TRODAT-1, [18F]-DOPA, [18F]-AV-133, and [18F]-FP-CIT. The most studied one and the one with the highest number of publications is [123I]-FP-CIT. Fludeoxyglucose (18F) revealed a specific pattern that could predict individuals susceptible to developing drug-induced parkinsonism. Another scintigraphy method is [123I]-MIBG cardiac imaging, in which a relationship between abnormal cardiac imaging and normal dopamine transporter imaging was associated with a progression to degenerative disease in individuals with drug-induced parkinsonism. Structural brain magnetic resonance imaging can be used to assess the striatal region. A transcranial ultrasound is a non-invasive method with significant benefits regarding costs and availability. Optic coherence tomography only showed abnormalities in the late phase of Parkinson's disease, so no benefit in distinguishing early-phase Parkinson's disease and drug-induced parkinsonism was found. Most methods demonstrated a high specificity in differentiating degenerative from non-degenerative conditions, but the sensitivity widely varied in the studies. An algorithm was designed based on clinical manifestations, neuroimaging, and drug dose adjustment to assist in the management of patients with drug-induced parkinsonism.

Brain-Biomarker Changes in Body Fluids of Patients with Parkinson's Disease.

Parkinson's disease (PD) is an incurable neurodegenerative disease that is rarely diagnosed at an early stage. Although the understanding of PD-related mechanisms has greatly improved over the last decade, the diagnosis of PD is still based on neurological examination through the identification of motor symptoms, including bradykinesia, rigidity, postural instability, and resting tremor. The early phase of PD is characterized by subtle symptoms with a misdiagnosis rate of approximately 16-20%. The difficulty in recognizing early PD has implications for the potential use of novel therapeutic approaches. For this reason, it is important to discover PD brain biomarkers that can indicate early dopaminergic dysfunction through their changes in body fluids, such as saliva, urine, blood, or cerebrospinal fluid (CSF). For the CFS-based test, the invasiveness of sampling is a major limitation, whereas the other body fluids are easier to obtain and could also allow population screening. Following the identification of the crucial role of alpha-synuclein (α-syn) in the pathology of PD, a very large number of studies have summarized its changes in body fluids. However, methodological problems have led to the poor diagnostic/prognostic value of this protein and alternative biomarkers are currently being investigated. The aim of this paper is therefore to summarize studies on protein biomarkers that are alternatives to α-syn, particularly those that change in nigrostriatal areas and in biofluids, with a focus on blood, and, eventually, saliva and urine.

Altered Motor Performance, Sleep EEG, and Parkinson's Disease Pathology Induced by Chronic Sleep Deprivation in Lrrk2G2019S Mice.

Parkinson's disease (PD) is a multifaceted disease in which environmental variables combined with genetic predisposition cause dopaminergic (DAergic) neuron loss in the substantia nigra pars compacta. The mutation of leucine-rich repeat kinase 2 (Lrrk2) is the most common autosomal dominant mutation in PD, and it has also been reported in sporadic cases. A growing body of research suggests that circadian rhythm disruption, particularly sleep-wake abnormality, is common during the early phase of PD. Our present study aimed to evaluate the impact of sleep deprivation (SD) on motor ability, sleep performance, and PD pathologies in Lrrk2G2019S transgenic mice. After two months of SD, Lrrk2G2019S mice at 12 months of age showed an exacerbated PD-like phenotype with motor deficits, a reduced striatal DA level, degenerated DAergic neurons, and altered sleep structure and biological rhythm accompanied by the decreased protein expression level of circadian locomotor output cycles kaput Lrrk2 gene in the brain. All these changes persisted and were even more evident in 18-month-old mice after 6 months of follow-up. Moreover, a significant increase in α-synuclein aggregation was found in SD-treated transgenic mice at 18 months of age. Taken together, our findings indicate that sleep abnormalities, as a risk factor, may contribute to the pathogenesis and progression of PD. Early detection of sleep disorders and improvement of sleep quality may help to delay disease progression and provide long-term clinical benefits.

NfL as a biomarker for neurodegeneration and survival in Parkinson disease.

ObjectiveTo determine whether neurofilament light chain protein in CSF (cNfL), a sensitive biomarker of neuroaxonal damage, reflects disease severity or can predict survival in Parkinson disease (PD).MethodsWe investigated whether disease severity, phenotype, or survival in patients with new-onset PD correlates with cNfL concentrations around the time of diagnosis in the population-based New Parkinsonism in Umeå (NYPUM) study cohort (n = 99). A second, larger new-onset PD cohort (n = 194) was used for independent validation. Association of brain pathology with the cNfL concentration was examined with striatal dopamine transporter imaging and repeated diffusion tensor imaging at baseline and 1 and 3 years.ResultsHigher cNfL in the early phase of PD was associated with greater severity of all cardinal motor symptoms except tremor in both cohorts and with shorter survival and impaired olfaction. cNfL concentrations above the median of 903 ng/L conferred an overall 5.8 times increased hazard of death during follow-up. After adjustment for age and sex, higher cNfL correlated with striatal dopamine transporter uptake deficits and lower fractional anisotropy in diffusion tensor imaging of several axonal tracts.ConclusionscNfL shows usefulness as a biomarker of disease severity and to predict survival in PD. The present results indicate that the cNfL concentration reflects the intensity of the neurodegenerative process, which could be important in future clinical trials.Classification of evidenceThis study provides Class II evidence that in patients with PD, cNfL concentrations are associated with more severe disease and shorter survival.

Progression of grey and white matter brain damage in Parkinson's disease: a critical review of structural MRI literature

The current review summarizes the current knowledge on longitudinal cortical and subcortical grey and white matter MRI findings assessed using T1-weighted and one-tensor diffusion-weighted MRI in Parkinson's disease (PD) patients. Results were reviewed according to disease duration, disease severity and cognitive impairment. The most consistent findings are those showing a progressive cortical atrophy accumulation in caudate, putamen, temporal/hippocampal, frontal and parietal areas in de novo PD cases and in the early/middle phase of the disease, with the achievement of a plateau in the later stage. Analyzing results according to the patient cognitive status, only a few studies used longitudinal MRI metrics to predict mild cognitive impairment or dementia conversion in PD patients, suggesting that atrophy of the hippocampus, fronto-temporal areas, caudate, thalamus and accumbens might play a role in this process. Stratifying patients according to disease severity, findings appear partially controversial, although showing a progressive atrophy of basal ganglia over 1year of follow up and a widespread cortical thinning over 3-6years in mild to moderate PD patients. Finally, microstructural damage of the main motor and associative WM tracts seems to be present, and rapidly progress, even in the early phase of PD. The utility of structural MRI metrics as biomarkers of PD progression and their role in improving the accuracy of disease progression prediction is still debated.

Low plasma thiamine and phosphate in male patients with Parkinson's disease is associated with mild cognitive impairment

Thiamine deficiency (TD) and phosphate depletion increase the risk for cognitive disturbances. This study investigates whether plasma levels of thiamine (P-THIAM), thiamine-monophosphate (P-TMP), and phosphate (P-PHOS) are associated with mild cognitive decline (MCI) in patients with Parkinson's disease (PD). This case-control study includes baseline data from a cohort of newly diagnosed patients identified in the New Parkinsonism in Umeå study (NYPUM) (N=75) and an age and sex matched control group (n=24). Mini Nutritional Assessment (MNA-score) and concentrations of P-THIAM, P-TMP, and P-PHOS at baseline were compared between PD patients with mild cognitive impairment (PD-MCI) and PD patients with normal cognition (PD-NC). Neuropsychological assessments of MCI were performed at time of diagnosis. Compared to patients with NC, patients with MCI had lower levels of P-THIAM and P-TMP as well as lower scores on both the Mini Mental State Examination (MMSE) and MNA-screening test. In addition, patients with MCI were older and had more motor problems. The multiple logistic regressions adjusted for age and sex revealed that higher levels of P-THIAM and the MNA-total score were associated with a lower risk of having MCI. Higher MNA-total score and higher P-THIAM and P-PHOS concentrations decreased the risk of MCI in male patients, but not in female patients. The decreased risk of MCI with higher P-TMP levels was lost after adding age and sex to the model. Bivariate correlations between P-PHOS and P-TMP were shown for the total PD population and controls as well as for males with MCI (r=0.533; n=22; p=0.011), but not for males with NC (r=0.314; n=19; p=0.204). An inverse partial correlation (adjusted for age, sex and UPDRS III) was shown for P-THIAM and MNA-total (r=-0.315,p=0.009) and -final (part II) (r=-0.395,p=0.001) score for the PD population (n=75). Higher P-THIAM and P-PHOS concentrations and higher MNA-total score were associated with a lower risk of MCI in male PD patients, findings that indicate that nutritional factors may influence cognitive function in males in the early phase of PD.

Sensitivity and specificity of cardiac 123I-MIBG scintigraphy for diagnosis of early-phase Parkinson's disease

IntroductionThe purpose of this study was to investigate the diagnostic accuracy of cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy for the diagnosis of Parkinson's disease (PD), especially in the early stages. MethodsWe investigated 600 patients who underwent cardiac 123I-MIBG scintigraphy to diagnose their parkinsonism and/or cognitive impairment. Of 600 research subjects, 272 patients were clinically diagnosed with PD. MIBG uptake was compared between patients with PD and other diseases. Furthermore, the sensitivity and specificity of cardiac 123I-MIBG scintigraphy to diagnose PD was estimated by disease duration (<3 years: early group vs. over 3 years: late group). We also assessed the relationship between MIBG uptake and Hoehn & Yahr stage. ResultsMIBG uptakes of PD patients were significantly decreased compared with those of other diseases except dementia with Lewy bodies and pure autonomic failure (p < .05 for all). In the early group, the sensitivity and specificity of the delayed heart to mediastinum (H/M) ratio were 68.7% and 91.7%, respectively, while in the late group, the sensitivity was 86.3% and the specificity was 74.0%. In addition, the early and delayed H/M ratios were decreased with higher Hoehn & Yahr stages in PD patients. ConclusionOur findings demonstrated that cardiac 123I-MIBG scintigraphy had sufficient diagnostic accuracy to detect the early phase of PD. Indeed, this study of a large number of patients provides further external validation that MIBG has diagnostic ability to distinguish PD from atypical parkinsonism.

Combined Assessment of Diffusion Parameters and Cerebral Blood Flow Within Basal Ganglia in Early Parkinson's Disease.

Diffusion tensor imaging (DTI) is a sensitive tool for detecting brain tissue microstructural alterations in Parkinson’s disease (PD). Abnormal cerebral perfusion patterns have also been reported in PD patients using arterial spin labeling (ASL) MRI. In this study we aimed to perform a combined DTI and ASL assessment in PD patients within the basal ganglia, in order to test the relationship between microstructural and perfusion alterations. Fifty-two subjects participated in this study. Specifically, 26 PD patients [mean age (SD) = 66.7 (8.9) years, 21 males, median (IQR) Modified Hoehn and Yahr = 1.5 (1–1.6)] and twenty-six healthy controls [HC, mean age (SD) = 65.2 (7.5), 15 males] were scanned with 1.5T MRI. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) maps were derived from diffusion-weighted images, while cerebral blood flow (CBF) maps were computed from ASL data. After registration to Montreal Neurological Institute standard space, FA, MD, AD, RD and CBF median values were extracted within specific regions of interest: substantia nigra, caudate, putamen, globus pallidus, thalamus, red nucleus and subthalamic nucleus. DTI measures and CBF were compared between the two groups. The relationship between diffusion parameters and CBF was tested with Spearman’s correlations. False discovery rate (FDR)-corrected p-values lower than 0.05 were considered significant, while uncorrected p-values <0.05 were considered a trend. No significant FA, MD and RD differences were observed. AD was significantly increased in PD patients compared with HC in the putamen (p = 0.005, pFDR = 0.035). No significant CBF differences were found between PD patients and HC. Diffusion parameters were not significantly correlated with CBF in the HC group, while a significant correlation emerged for PD patients in the caudate nucleus, for all DTI measures (with FA: r = 0.543, pFDR = 0.028; with MD: r = −0.661, pFDR = 0.002; with AD: r = −0.628, pFDR = 0.007; with RD: r = −0.635, pFDR = 0.003). This study showed that DTI is a more sensitive technique than ASL to detect alterations in the basal ganglia in the early phase of PD. Our results suggest that, although DTI and ASL convey different information, a relationship between microstructural integrity and perfusion changes in the caudate may be present.

Usefulness of combining 123I-FP-CIT-SPECT striatal asymmetry index and cardiac 123I-metaiodobenzylguanidine scintigraphy examinations for diagnosis of parkinsonisms

BackgroundAlthough single-photon emission computerized tomography of the dopamine transporter (DAT-SPECT) is useful for diagnosing parkinsonian syndrome, its applicability toward the early phase of Parkinson's disease remains unknown. MethodsWe enrolled 32 patients showing parkinsonism with normal cardiac 123I-metaiodobenzylguanidine (MIBG) uptake and abnormal DAT-SPECT findings among 84 consecutive patients with parkinsonism. We divided these patients into two groups (group 1: Parkinson's disease, group 2: corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy), and compared their clinical characteristics, specific binding ratios, and striatal asymmetry indexes on DAT-SPECT examinations. ResultsThe striatal asymmetry indexes were significantly lower in group 1 than in group 2 (p<0.05), but there were no differences in the specific binding ratios between the two groups. ConclusionThe combined use of striatal asymmetry index on DAT-SPECT and cardiac MIBG scintigraphy might offer useful clues for the differential diagnosis of the early phase Parkinson's disease from other parkinsonian syndromes.

DJ-1 as a Biomarker of Parkinson's Disease.

Parkinson's disease is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ-1 has been identified as a causative gene of a familial form of Parkinson's disease, PARK7, and plays a significant role in antioxidative defense, protecting cells from oxidative stress. A cysteine residue of DJ-1 at position 106 (Cys-106) is preferentially oxidized under oxidative stress. This reactive Cys-106 plays a critical role in the biological function of DJ-1, which could act as a sensor of oxidative stress by regulating antioxidative defense depending on Cys-106 oxidation. Thus, the levels of Cys-106-oxidized DJ-1 (oxDJ-1) could be a possible biomarker of oxidative stress. This chapter focuses on the properties of DJ-1 and oxDJ-1 levels as a biomarker of Parkinson's disease. In particular, the usability of these biomarkers to prevent and treat this neurodegenerative disease is discussed. Further, this section deals with the importance of identifying a biomarker of early-phase Parkinson's disease. Finally, this chapter summarizes the features of oxDJ-1 levels in the brain and blood as a biomarker candidate for early-phase Parkinson's disease based on our results using oxDJ-1-specific antibodies.

Cardiac parasympathetic dysfunction in the early phase of Parkinson's disease.

Cardiac parasympathetic function is strongly affected by aging. Although sympathetic dysfunction has been well documented in Parkinson's disease (PD), cardiac parasympathetic dysfunction has not been well studied. The objective of this study was to clarify the development of cardiac parasympathetic dysfunction in the early phase of PD and to explore the age-corrected correlation between cardiac parasympathetic dysfunction and cardiac sympathetic dysfunction. We reviewed 25 healthy controls and 56 patients with idiopathic PD of Hoehn and Yahr stages I-III. We evaluated cardiac parasympathetic function using the Valsalva ratio, the baroreflex sensitivity (BRS) and the coefficient of variation of RR intervals in the resting state (resting-CVRR) and during deep breathing (DB-CVRR). In addition, we measured cardiac 123I-metaiodobenzylguanidine (MIBG) uptake to investigate the relationship between cardiac sympathetic and parasympathetic dysfunction in PD. Compared with healthy controls, patients with PD showed significantly decreased cardiac parasympathetic parameters (resting-CVRR 2.8±1.3 vs. 1.7±0.6%, p<0.001; DB-CVRR 5.8±2.3 vs. 3.8±1.7%, p<0.001; Valsalva ratio 1.52±0.26 vs. 1.34±0.17, p<0.01; BRS 10.6±9.5 vs. 5.0±5.4ms/mmHg, p<0.01). In particular, resting-CVRR and DB-CVRR were significantly decreased in the early phase of PD. In age-corrected analyses, none of the parasympathetic indices correlated with the delayed cardiac 123I-MIBG uptake. These observations indicate that cardiac parasympathetic dysfunction occurs in the early phase of PD, but not necessarily in parallel with cardiac sympathetic dysfunction.

Caffeine consumption and the 4-year progression of de novo Parkinson's disease

IntroductionHigher caffeine consumption has been associated with reduced risk of Parkinson's disease (PD), and with a more benign progression of motor and non-motor symptoms (NMS). The present observational cohort study investigated motor and non-motor correlates of caffeine consumption in de novo PD. Methods79 newly diagnosed, drug naïve PD patients have been included and followed up for 4 years. The total caffeine use was calculated with the Caffeine Consumption Questionnaire. Following study variables were recorded at baseline, and after 2 and 4 years: UPDRS part III, UPDRS part IV, l-dopa Equivalent Daily Dose (LEDD), NMS Questionnaire (NMSQuest), and the time occurring from PD diagnosis to the need for l-dopa treatment. Age, gender and disease duration were included as covariates in the statistical models. ResultsThe average daily caffeine consumption was 296.1 ± 157.2 mg. At Cox regression models, higher caffeine consumption was associated with a lower rate of starting l-Dopa treatment (HR = 0.630; 95%CI = 0.382–0.996). At the mixed-effects linear regression models considering the whole study period, each additional espresso cup per day (50 mg of caffeine) was more likely associated with 5-point lower UPDRS part III total score (Coef = −0.01; 95%CI = −0.02 to 0.00), with 50% reduced LEDD (Coef = −0.01; 95%CI = −0.15 to 0.00; p = 0.021), and with 5-point lower NMSQuest total score (Coef = −0.01; 95%CI = −0.01 to 0.00), but not with UPDRS part IV total score (Coef = −0.00; 95%CI = −0.00 to 0.00). ConclusionCaffeine consumption was associated with a reduced accrual of motor and non-motor disability during 4-year follow-up in de novo PD, highlighting the rationale for using adenosine A2A antagonists since the early phases of PD.

Somatosensory temporal discrimination threshold in Parkinson's disease parallels disease severity and duration.

To investigate whether the somatosensory temporal discrimination threshold (STDT) is already altered at the clinical onset of Parkinson's disease (PD) and whether STDT abnormalities correlate with disease progression we tested STDT values in patients with different severity of disease. We prospectively and consecutively enrolled 63 PD patients: 26 drug-naive PD patients with symptom onset no longer than two years prior to inclusion in the study (early-phase), 37 PD patients with varying degrees of disease severity and 51 age-matched healthy subjects. The STDT was tested on the index finger of both hands, and on both sides of the face. Twelve out of 26 early phase PD patients were re-tested two years after the initial diagnosis. PD patients as a whole displayed higher STDT values than healthy subjects. STDT values did not significantly differ between early-phase PD patients and healthy subjects, whereas they were significantly higher in patients with mild/moderate and advanced PD. In early-phase PD patients STDT values at the two years-follow up assessment did not statistically differ from those obtained at baseline. Considering the whole group of PD patients STDT abnormalities significantly correlated with duration and severity of the disease. STDT increases as disease progresses. In early-phase PD patients STDT values are still statistically similar to those of healthy subjects, thus implying that dopaminergic depletion alone may not be sufficient to cause STDT abnormalities. Our study gives new insight into the sensory abnormalities in PD.

Diagnostic value of combined assessment of olfaction and substantia nigra hyperechogenicity for Parkinson's disease

IntroductionHyposmia and substantia nigra hyperechogenicity (SN+) are characteristic markers of Parkinson's disease (PD), although their diagnostic value in isolation may be limited. We evaluated the combined prevalence of both disorders in patients diagnosed with PD and assessed their diagnostic yield compared to a sample with essential tremor (ET) and another group of healthy subjects. MethodsPatients diagnosed with PD and ET and treated in our outpatient clinic were enrolled. Olfaction was assessed using the “Sniffin Sticks” odour identification test (SS-12) and hyperechogenicity of the substantia nigra (SN+) was assessed by transcranial duplex ultrasound. ResultsA total of 98 subjects were analysed, comprising 30 with PD, 21 with ET, and 47 controls. The respective prevalence rates of hyposmia (SS-12<8) and SN+ (area>0.24cm2) were 70% and 83.3% in PD, 33.3% and 9.5% in ET, and 17% and 10.6% in controls. Both markers were present in 63% of patients with PD, none of the patients with ET, and only 2 of the controls. ConclusionsCombined use of substantia nigra sonography and olfactory testing with SS-12, two rapid, safe, and accessible tests, was more specific than each isolated marker for distinguishing patients with PD from patients with ET and control subjects. Since both markers have been described in very early phases of PD, combined use may be helpful in providing early diagnosis of PD.

Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients.

Non-motor symptoms burden in treated and untreated early Parkinson's disease patients: argument for non-motor subtypes.

Non-motor symptoms (NMSs) occurring at an early stage of Parkinson's disease (PD) may impair quality of life more than motor symptoms. This study aimed to evaluate the severity of overall NMS profile and burden of NMSs in early PD patients, treated (time since confirmed diagnosis of 5 years or less) or drug naive (DN). Cross-sectional data from an ongoing multicentre study (16 sites) were obtained and specifically an NMS data set from validated scales was analysed in treated and DN PD patients. A full data set was available in 234 unique early PD patients. Of them, there were 170 treated (63.5% males, mean age 68.2 years) and 64DN patients (64.1% males, mean age 66.5 years). Compared to DN patients the time since confirmed diagnosis was significantly longer in treated PD patients (1.9 years vs. 3.7 years, P < 0.001). Fatigue (57.7%), urinary urgency (57.1%), nocturia (55.3%), memory difficulties (51.2%) and urinary frequency (48.8%) were the most prevalent NMSs amongst treated PD, whereas DN PD reported most frequently sadness (57.8%), fatigue (57.8%), lightheadedness (53.1%), memory difficulties (48.4%) and urinary urgency (46.9%). Our results suggest that NMSs are dominant in the untreated and early phase of PD causing a considerable burden. This warrants investigation of the issue of NMS subtyping within PD.

Increased bilirubin levels in de novo Parkinson's disease.

Oxidative stress is a central pathogenic mechanism of Parkinson's disease (PD), and the heme oxygenase (HO) bilirubin pathway is one of the main mammalian antioxidative defences. Indeed, there is growing evidence of HO-bilirubin upregulation from early phases of PD. Our aim was to investigate bilirubin as a possible biomarker of PD diagnosis and progression. A cross-sectional case-control study was performed to evaluate differences in bilirubin levels between newly diagnosed, drug-naïve PD subjects and controls. Afterwards, PD subjects were included in a 2-year longitudinal study to evaluate disease progression in relation to baseline bilirubin levels. Seventy-five de novo PD subjects were selected and matched with 75 controls by propensity score. Analysis of variance showed higher bilirubin levels in PD patients compared with controls (P < 0.001). Linear regression analysis failed to show a relationship between bilirubin and Unified Parkinson's Disease Rating Scale (UPDRS) part III (P = 0.283) at baseline evaluation. At 2-year follow-up, indirect relationships between bilirubin levels and UPDRS part III (P = 0.028) and between bilirubin levels and levodopa-equivalent daily dosage (P = 0.012) were found. Parkinson's disease subjects showed higher levels of bilirubin compared with controls. Bilirubin increase might be due to HO overexpression as a compensatory response to oxidative stress occurring from early stages of PD.

Applause sign in advanced Parkinson's disease.

The 'applause sign' a tendency to continue applauding in response to instructions to clap three times was described in 1995 and was considered specific to degenerative disease, especially to atypical parkinsonian disorders. In early phase Parkinson's disease (PD) the sign has been reported positive as well. In late stage PD it is unknown whether and to what extent the sign may be elicited and it remains unknown if and to what degree the sign correlates to cognitive impairment and PD related dementia. Nursing home residents with PD (MMSE >17) were included. All patients underwent the clapping test and were tested for cognitive disturbance by making use of accepted clinimetrics (MMSE and Scopa-cog). T-testing was performed with the hypothesis that patients expressing the applause sign would score lower on the MMSE or Scopa-cog. Seventy three nursing home residents (mainly Hoehn and Yahr 4/5) with a mean disease duration of 10 years and a mean age of 78.7 years were included. The applause sign was found positive in 15 of 73 residents (20.5%). Residents expressing the applause sign had significantly lower mean scores on the MMSE (25.1 vs 22.9 points, p<0.006) and Scopa-cog (14.8 vs 12.0 points, p<0.039). The applause sign is present in late stage PD and correlates with a higher degree of cognitive impairment as established with accepted clinimetric tests. A higher degree of frontal lobe involvement explains the presence of the applause sign.

Longitudinal changes in task-evoked brain responses in Parkinson's disease patients with and without mild cognitive impairment.

Cognitive deficits are common in Parkinson's disease. Previous cross-sectional research has demonstrated a link between cognitive impairments and fronto-striatal dopaminergic dysmodulation. However, longitudinal studies that link disease progression with altered task-evoked brain activity are lacking. Therefore, our objective was to longitudinally evaluate working-memory related brain activity changes in Parkinson's disease patients with and without mild cognitive impairment (MCI). Patients were recruited within a longitudinal cohort study of incident patients with idiopathic parkinsonism. We longitudinally (at baseline examination and at 12-months follow-up) compared 28 patients with Parkinson's disease without MCI with 11 patients with Parkinson's disease and MCI. Functional MRI blood oxygen level dependent signal was measured during a verbal two-back working-memory task. Patients with MCI under-recruited bilateral medial prefrontal cortex at both time-points (main effect of group: p < 0.001, uncorrected). Critically, a significant group-by-time interaction effect (p < 0.001, uncorrected) was found in the right fusiform gyrus, indicating that working-memory related activity decreased for patients with Parkinson's disease and MCI between baseline and follow-up, while patients without MCI were stable across time-points. The functional connectivity between right fusiform gyrus and bilateral caudate nucleus was stronger for patients without MCI relative to patients with MCI. Our findings support the view that deficits in working-memory updating are related to persistent fronto-striatal under-recruitments in patients with early phase Parkinson's disease and MCI. The longitudinal evolution of MCI in Parkinson's disease translates into additional task-evoked posterior cortical changes.