A quantitative comparison of basal ganglia neuronal activities of normal and Parkinson's disease model rats

The purpose of this study was to identify consistent characteristic changes of neuronal activity in basal ganglia (BG) nuclei associated with Parkinson's disease (PD) so that a reliable index of PD can be derived. A simple algorithm for automatic identification of firing patterns was devised as an essential tool to achieve this goal. A detailed quantitative analysis of firing patterns as well as firing rate was performed in three BG nuclei: the subthalamic nucleus (STN), the substantia nigra pars reticulate (SNpr), and the globus pallidus (GP). The results showed that the firing rate of STN neurons was not significantly altered in PD model rats. We also did not find a significant alteration in firing rates in the SNpr and GP between normal and PD model rats. In contrast, consistent changes of firing patterns were observed in all three BG nuclei in that the percentage of neurons with a regular firing pattern decreased whereas those with irregular, mixed, or burst patterns increased. This enables a simple algorithm based on burst detection and the shape of the interspike interval histogram to identify whether the neuronal activity is from normal or PD model rats.     

The Mediating Effect of Insomnia on the Relationship between Panic Symptoms and Depression in Patients with Panic Disorder

BackgroundThis study aimed to determine if sleep disturbances may mediate the relationship between panic symptoms and depression in patients with panic disorder (PD).MethodsElectronic medical records were retrospectively reviewed for 110 consecutive patients with diagnosed PD in an outpatient clinic between October 2018 and December 2019. Measurements include the PD Severity Scale, Beck Depression Inventory-II (BDI-II) and Insomnia Severity Index (ISI). Statistical analyses were performed to assess any potential relationship between PD, insomnia and depression.ResultsOf the PD patients, 88 (80%) and 89 (80.9%) had comorbid depression (BDI-II ≥ 14) and insomnia (Korean version of the ISI ≥ 8), respectively. In a mediation model using insomnia as the mediating variable, the total effect of panic symptom severity on depression was significant (t = 7.23, P < 0.001). There were significant effects of panic symptoms on insomnia (t = 4.62, P < 0.001) and of insomnia on depression (t = 6.69, P < 0.001). The main effect of panic symptom severity on depression was also significant, after controlling for the effect of insomnia (t = 5.10, P < 0.001), suggesting partial mediation.ConclusionBoth depressive symptoms and insomnia are common in patients with PD and depression was partially mediated by insomnia in these patients. These results suggest that an intervention for insomnia in patients with PD might help prevent the development of depression.     

Subjective poor sleep quality in Chinese patients with Parkinson's disease without dementia

Parkinson''s disease (PD) is a common progressive neurological disorder and is composed of motor and non-motor symptoms. Sleep disturbances are frequent problems for patients with PD. The relationship between sleep disturbances with Hoehn and Yahr (H&Y) staging have been demonstrated. However, the relationship between sleep disorders and H&Y is still unclear in patients with PD without dementia in Chinese PD patients. In this study, we interviewed 487 non-demented PD patients of Chinese Han descents by H&Y classification. We found that night sleep quality was significantly associated with the severity of PD (P = 0.008). Panic disorder severity scale (PDSS) total scores were correlated with PD non-motor symptoms scale (PDNMS) scores (r = -0.528, P < 0.001), the Hamilton depression scale (HAMD) scores (r = -0.545, P < 0.001) and the Hamilton anxiety scale (HAMA) scores (r = -0.498, P < 0.001). Our results indicated that sleep quality deteriorated with the advancing of PD in Chinese non-demented patients with PD. Depression and anxiety may partly explain sleep disturbances in non-demented patients with PD.     

Lack of replication of a previously reported association between polymorphism in the 3′UTR of the alpha-synuclein gene and Parkinson's disease in Chinese subjects

Recent studies have implicated polymorphisms in the 3′ untranslated region (3′UTR) of the alpha-synuclein (SNCA) gene in the development of Parkinson's disease (PD). Single nucleotide polymorphism (SNP) rs356165 is one of polymorphisms located in the 3′UTR and its association with PD has been reported but remains controversial. Herein, we conducted a case-control study to further evaluate the possible association between SNP rs356165 and PD in Chinese. All subjects (330 PD patients and 300 normal controls) were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No statistically significant difference in genotype frequency between cases and controls was observed (P = 0.863), suggesting no association of SNP rs356165 with PD in our population. Thus, it may be premature to conclude an association between the 3′UTR of the SNCA gene and PD, and this association should be further examined in different ethnic populations.     

The validity of the severity-psychosis hypothesis in depression

BackgroundPsychotic depression (PD) is classified as a subtype of severe depression in the current diagnostic manuals. Accordingly, it is a common conception among psychiatrists that psychotic features in depression arise as a consequence of depressive severity. The aim of this study was to determine whether the severity of depressive and psychotic symptoms correlate in accordance with this “severity–psychosis” hypothesis and to detect potential differences in the clinical features of PD and non-psychotic depression (non-PD).MethodsQuantitative analysis of Health of the Nation Outcome Scales (HoNOS) scores from all patients admitted to a Danish general psychiatric hospital due to a severe depressive episode in the period between 2000 and 2010 was performed.ResultsA total of 357 patients with severe depression, of which 125 (35%) were of the psychotic subtype, formed the study sample. Mean HoNOS scores at admission differed significantly between patients with non-PD and PD on the items hallucinations and delusions (non-PD = 0.33 vs. PD = 1.37, p < 0.001), aggression (non-PD = 0.20 vs. PD = 0.36, p = 0.044) and on the total score (non-PD = 10.55 vs. PD = 11.87, p = 0.024). The HoNOS scores on the two items “depression” and “hallucinations and delusions” were very weakly correlated.LimitationsDiagnoses were based on normal clinical practice and not formalized research criteria.ConclusionsThe symptomatology of PD and non-PD differs beyond the mere psychosis. Furthermore, severity ratings of depressive and psychotic symptoms are very weakly correlated. These findings offer further support to the hypothesis stating that the psychotic- and non-psychotic subtypes of depression may in fact be distinct clinical syndromes.     

Serum (1 → 3)-β-d-glucan measurement as an early indicator of Pneumocystis jirovecii pneumonia and evaluation of its prognostic value

Pneumocystis jirovecii (carinii) pneumonia (PJP) is a major cause of disease in immunocompromised individuals. However, until recently no reliable and specific serological parameters for the diagnosis of PJP have been available. (1 → 3)-β-d-Glucan (BG) is a cell wall component of P. jirovecii and of various other fungi. Data from the past few years have pointed to serum measurement of BG as a promising new tool for the diagnosis of PJP. We therefore conducted a retrospective study on 50 patients with PJP and 50 immunocompromised control patients to evaluate the diagnostic performance of serum BG measurement. Our results show an excellent diagnostic performance with a sensitivity of 98.0% and a specificity of 94%. While the positive predictive value was only 64.7%, the negative predictive value was 99.8% and therefore a negative BG result almost rules out PJP. BG levels were already strongly elevated in an average of 5 days and up to 21 days before microbiological diagnosis demonstrating that the diagnosis could have been confirmed earlier. BG levels at diagnosis and maximum BG levels during follow-up did not correlate with the outcome of patients or with the P. jirovecii burden in the lung as detected by Real-Time PCR. Therefore, absolute BG levels seem to be of no prognostic value. Altogether, BG is a reliable parameter for the diagnosis of PJP and could be used as a preliminary test for patients at risk before a bronchoalveolar lavage is performed.     

Dyskinetic Parkinson’s disease patients demonstrate motor abnormalities off medication

The pathophysiology of l-dopa-induced dyskinesias (LIDs) in Parkinson’s disease (PD) remains poorly understood. The presence of superimposed LIDs clearly differentiates motor performance of dyskinetic from non-dyskinetic PD subjects when they are on medication, but here, we investigated whether their respective motor performance differs while subjects are off l-dopa medication and LIDs are not apparent. We assessed the motor performance of nine dyskinetic and ten non-dyskinetic PD subjects off l-dopa, and of ten age-matched control subjects, during a visually guided tracking task. As previous studies have suggested that linear dynamical system (LDS) models are useful to assess motor performance in PD in addition to overall tracking error, we used LDS models to assess the damping ratio parameter of motor behavior while controlling for disease severity. While overall tracking error did not significantly differ across groups, dyskinetic PD subjects demonstrated a significantly decreased mean damping ratio compared with control and non-dyskinetic PD subjects. For both groups, greater disease severity significantly predicted a lower damping ratio, but even after controlling for disease severity, the damping ratio for dyskinetic subjects was significantly lower. Our results demonstrate, somewhat counter-intuitively, that motor performance of dyskinetic and non-dyskinetic PD subjects differ, even off l-dopa when no dyskinesias are seen. A decreased damping ratio is indicative of a tendency to overshoot a target during motor performance, similar to the dysmetria found in cerebellar patients. We discuss the possibility of motor abnormalities in dyskinetic PD patients off medication in relation to altered functional cerebellar changes described in PD.     

Velocity control in Parkinson’s disease: a quantitative analysis of isochrony in scribbling movements

An experiment was conducted to contrast the motor performance of three groups (N = 20) of participants: (1) patients with confirmed Parkinson Disease (PD) diagnose; (2) age-matched controls; (3) young adults. The task consisted of scribbling freely for 10 s within circular frames of different sizes. Comparison among groups focused on the relation between the figural elements of the trace (overall size and trace length) and the velocity of the drawing movements. Results were analysed within the framework of previous work on normal individuals showing that instantaneous velocity of drawing movements depends jointly on trace curvature (Two-thirds Power Law) and trace extent (Isochrony principle). The motor behaviour of PD patients exhibited all classical symptoms of the disease (reduced average velocity, reduced fluency, micrographia). At a coarse level of analysis both isochrony and the dependence of velocity on curvature, which are supposed to reflect cortical mechanisms, were spared in PD patients. Instead, significant differences with respects to the control groups emerged from an in-depth analysis of the velocity control suggesting that patients did not scale average velocity as effectively as controls. We factored out velocity control by distinguishing the influence of the broad context in which movement is planned—i.e. the size of the limiting frames—from the influence of the local context—i.e. the linear extent of the unit of motor action being executed. The balance between the two factors was found to be distinctively different in PD patients and controls. This difference is discussed in the light of current theorizing on the role of cortical and sub-cortical mechanisms in the aetiology of PD. We argue that the results are congruent with the notion that cortical mechanisms are responsible for generating a parametric template of the desired movement and the BG specify the actual spatio-temporal parameters through a multiplicative gain factor acting on both size and velocity. An erratum to this article can be found at     

No association of the LRRK2 genetic variants with Alzheimer's disease in Han Chinese individuals

The leucine-rich repeat kinase–2 (LRRK2) gene has been regarded as 1 of the most common genetic causes of Parkinson's disease (PD). We hypothesized that LRRK2-susceptible allele(s) for PD might pose a risk for Alzheimer's disease (AD). In this study, we screened 12 LRRK2 gene variants in 2 independent cohorts from southwestern China (341 AD patients and 435 normal individuals) and eastern China (297 AD patients and 384 normal individuals), to discern the potential association between this gene and AD. No variant was identified to be associated with AD in either case-control sample. As both of the cohorts were of Han Chinese origin, we combined the LRRK2 variant data for the 2 sample sets together (a total of 638 AD patients and 819 normal individuals) and still found no association between the LRRK2 gene and AD, suggesting that LRRK2 gene variants may not affect the development of AD in Han Chinese individuals.     

Fractal organization of the pointwise correlation dimension of the heart rate

Objective: To depict and quantify the degree of organization of the heart rate variability (HRV) in normal subjects. Methods: A modified algorithm was created to estimate series of ‘point-dimensions’ (PD2) from interbeat (R-R) interval series of 10 healthy subjects (21–56 years). Our innovation is twofold: (i) we quantified instances of low-dimensional chaos, random fluctuations, and those for which our method failed to provide either (due to poor statistics); (ii) consecutive subepochs of PD2s underwent a relative dispersion (RD) analysis, yielding an index (D) which quantifies the dynamical organization of the heart rate generator.Results: The mean values of PD2 series varied between 4.58 and 5.88 (mean ± SD= 5.21 ± 0.41, n = 10). For group 1 (21–30 years, n = 6) we found an averaged PD2 of 5.49 ± 0.27, while for group 2 (47–56 years, n = 4) PD2 averaged 4.79 ± 0.17. The RD analysis performed for subepochs of PD2s yielded both instances obeying fractal scaling (D < 1.5) and stochasticity (D > 1.5). The average D for group 1 was 1.39 ± 0.04 (14 subepochs) and for group 2, 1.20 ± 0.008 (8 subepochs). Paired t-test and Hartley F-max test for comparison between D values and homogeneity of variance between the two groups were performed, yielding P-values 0.004 and 0.02, respectively.Conclusions: The complexity of the HRV seems to be modulated by a non-random fractal mechanism of a ‘hyperchaotic’ system, i.e. it can be hypothesized to contain more than one attractor. Also, our results support the ‘chaos hypothesis’ put forth recently, namely, the complexity of the cardiovascular dynamics is reduced with aging. The index of relative dispersion of the dimensional complexity has to be tested in various clinico-pathological settings, in order to corroborate its value as a potential new physiological measure.     

The effect of mesoporous bioactive glass on the physiochemical,biological and drug-release properties of poly(dl-lactide-co-glycolide) films

Poly(lactide-co-glycolide) (PLGA) has been widely used for bone tissue regeneration. However, it lacks hydrophilicity, bioactivity and sufficient mechanical strength and its acidic degradation by-products can lead to pH decrease in the vicinity of the implants. Mesoporous bioactive glass (MBG) with highly ordered structure (pore size 2–50 nm) possesses higher bioactivity than non-mesoporous bioactive glass (BG). The aim of this study is to investigate the effect of MBG on the mechanical strength, in vitro degradation, bioactivity, cellular response and drug release of PLGA films and optimize their physicochemical, biological and drug-delivery properties for bone tissue engineering application. The surface and inner microstructure, mechanical strength and surface hydrophilicity of MBG/PLGA and BG/PLGA films were tested. Results indicated that MBG or BG was uniformly dispersed in the PLGA films. The incorporation of MBG into PLGA films significantly improved their tensile strength, modulus and surface hydrophilicity. MBG/PLGA resulted in an enhanced mechanical strength, in vitro degradation (water absorbance, weight loss and ions release), apatite-formation ability and pH stability in simulated body fluids (SBF), compared to BG/PLGA. MBG/PLGA and BG/PLGA films enhanced human osteoblastic-like cells (HOBs) attachment, spreading and proliferation compared to PLGA. HOBs differentiation was significantly upregulated when cells were cultured on 30 MBG/PLGA for 14 days, compared to 30 BG/PLGA. MBG/PLGA enhanced the accumulative release of dexamethazone (DEX) at early stages (0–200 h) compared to BG/PLGA, however, after 200 h, DEX-release rates for MBG/PLGA was slower than that of BG/PLGA. The contents of MBG in PLGA films can control the amount of DEX released. Taken together, MBG/PLGA films possessed excellent physicochemical, biological and drug-release properties, indicating their potential application for bone tissue engineering by designing 3D scaffolds according to their corresponding compositions.     

A Tryptophan Hydroxylase 2 Gene Polymorphism is Associated with Panic Disorder

Panic disorder (PD) is a complex and heterogeneous psychiatric condition. Dysfunction within the serotonergic system has been hypothesized to play an important role in PD. The novel brain-specific serotonin synthesizing enzyme, tryptophan hydroxylase 2 (TPH2), which represents the rate-limiting enzyme of serotonin production in the brain, may therefore be of particular importance in PD. We investigated the TPH2 703G/T SNP for association with PD. Patients with PD (n = 108), and control subjects (n = 247), were genotyped for rs4570625 (TPH2 703G/T). Male and female subjects were analyzed separately. The severity of their symptoms was measured using the Spielberger state-trait anxiety inventory (STAI), panic disorder severity scale (PDSS), anxiety sensitivity index (ASI), acute panic inventory (API), and Hamilton’s rating scale for depression (HAMD). The genotype and allele frequencies of the PD patients and controls were analyzed using χ ² statistics. There was a significant difference in the allele frequency in rs4570625 between the PD patients and normal controls. The T allele was significantly less frequent in the PD patients. We also found a significant association with rs4570625 in the female subgroup. There was no difference in symptom severity among the genotypes of this polymorphism. This result suggests that rs4570625 polymorphism may play a significant role in the pathogenesis of PD. Moreover, rs4570625 may have a gender-dependent effect on susceptibility to PD. Further studies are needed to replicate the association that we observed. Edited by Tatiana Foroud.     

Plasma levels of DJ-1 as a possible marker for progression of sporadic Parkinson's disease

DJ-1 is a multifunctional protein whose loss of function by gene mutations may play a causative role for familial Parkinson's disease (PD). A recent study has shown that the expression of this molecule is upregulated in both brains and cerebrospinal fluids (CSF) in various neurological disorders, including sporadic PD, Alzheimer's disease (AD) and stroke, raising a possibility that DJ-1 could be a potential biomarker for these diseases. In this context, the main objective of the present study was to determine if DJ-1 was increased in the plasma of PD patients. For this purpose, blood plasma samples collected from sporadic PD patients, dementia with Lewy bodies (DLB) and healthy age-matched controls were analyzed by immunoblotting and enzyme-linked immunosorbent assay. The results showed that the plasma DJ-1 levels in PD (n = 104) were higher than those in control (n = 80) (p < 0.05). Moreover, the plasma DJ-1 levels in the advanced stage of PD (n = 52, Yahr III–IV) were higher than those in the early stage of PD (n = 52, Yahr I–II) (p < 0.05), demonstrating that the plasma DJ-1 was correlated with the disease severity in PD. Plasma DJ-1 levels were also significantly higher in DLB (n = 30) compared with both controls and early stage of PD (p < 0.01). Taken together, these results suggest that the plasma DJ-1 could be a useful biomarker for the evaluation of the disease severity in PD and possibly in other Lewy body diseases.     

Novel parameters indicate significant differences in severity of obstructive sleep apnea with patients having similar apnea–hypopnea index

Sleep apnea–hypopnea syndrome (SAHS) causes impairment of daytime functions and increases risk of cardiovascular diseases. Apnea–hypopnea index (AHI), currently used for the estimation of the severity of SAHS, does not contain information on the morphology or duration aspects of the breathing cessations and related oxygen desaturations. Longer breathing cessations and deeper desaturations may have more severe consequences than shorter and shallower ones. To address these issues, novel parameters containing information on the duration and morphology of breathing cessations and oxygen desaturations were calculated and evaluated on 160 male patients (40 patients in normal, mild, moderate and severe AHI severity categories). Obstruction and desaturation duration parameters consist of sum of event durations normalized with the total analysed time. Desaturation severity is a sum of desaturation event areas normalized with total analysed time and obstruction severity parameter is a sum of the products of apnea and hypopnea durations and related desaturation areas normalized with total analysed time. The median follow-up time of the patients was 183 months (range 154–215 months). The 40 patients in each category were further divided into subgroups A and B with lowest and highest novel parameter values, respectively. AHI showed no differences between the subgroups. Mortality was increased in subgroups B compared to subgroups A. The correlation of the novel parameters with AHI was only moderate and the parameter values were partially overlapping between the AHI severity categories. This suggests that patients with similar AHI may in fact suffer from SAHS of very different severity. Thus, the present results suggest that the novel parameters could bring new insight to the individual estimation of the severity of SAHS.     

Multihost, Multiparasite systems: An application of bifurcation theory

Author to whom all correspondence should be addressed (email: j.v.greenman{at}stir.ac.uk). The local analysis of multihost multiparasite models has beenhampered by algebraic intractability. There have been two responsesto this difficulty: extensive numerical investigation, and simplificationto a level where analytical techniques work. In this paper wedescribe another approach, based on bifurcation theory, in whichthe qualitative properties of the model equilibrium structureare realized on an array of maps drawn in parameter space. Thisapproach is described in the context of two models: the basictwo-host shared microparasite S–I model and the single-hosttwo-microparasite S–I (susceptible-infective) model. Theprocedure involved does not require model simplification througha reduction in dimensionality. It can handle intraspecific aswell as parasite-mediated competition and, in the second model,single-host parasite coexistence. The map arrays provide a concisecatalogue of the possible modes of behaviour of a system andan explanation for changes in that behaviour. In particular,the reasons why the conjectures made about the behaviour ofthe first of these models do not hold throughout parameter spaceare immediately clear from the map structure, as are the conditionsfor collusive and competitive behaviour between the two typesof parasite in the second model.     

From single extracellular unit recording in experimental and human Parkinsonism to the development of a functional concept of the role played by the basal ganglia in motor control

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects the whole basal ganglia (BG). Various techniques have been used to study BG physiology and pathophysiology. Among these, extracellular single unit recording remains of particular importance. An impressive number of studies of BG electrophysiological activity have been carried out, both in non-human and in human primates, but the data collected show many omissions and disparities. BG activity has been well defined in the physiological situation, but remains far from clear in the Parkinsonian and virtually unexplored in the dopamine (DA)-replacement situation. This paper provides a brief synopsis of (i) recording techniques and (ii) BG electrophysiological activity in normal, Parkinsonian, and dopamine-replacement situations. We have restricted the data used to those obtained in BG structures of human and non-human primates. Only single unit recordings have been reported and four electrophysiological characteristics retained: mean firing frequency, firing pattern, periodic oscillation, and response to both passive and active movement. We have attempted to summarize (i) the commonly accepted characteristics of each BG structure in the three situations, (ii) discrepancies that exist, and (iii) missing elements. Then, the main successive theories aimed to explain the role played by BG in motor control are presented and discussed in the light of the most recently obtained results using the latest technological advances.