Differential time- and frequency-dependent structure of postural sway and finger tremor in Parkinson's disease

The time- and frequency-dependent patterns of standing balance centre of pressure (COP) and finger postural/resting tremor of 12 older individuals and eight age-matched Parkinsonian (PD) participants (on/off medication) were investigated. Tremor and COP data were analysed using measures of signal amplitude (RMS), time-dependent structure (approximate entropy, ApEn), time-frequency analysis and synchrony (Cross ApEn). Results showed that the PD individuals had significantly greater tremor amplitude and COP excursions in comparison to controls. Differences in the time-dependent structure were also observed between groups. In comparison to the elderly, the resting/postural tremor output of the PD subjects was more regular (lower ApEn). However, for the postural measures, a reciprocal pattern was observed with the COP being more complex (higher ApEn). All group differences were magnified when the PD individuals were off their medication. There was also greater synchrony between tremor and postural sway for the PD individuals, indicating a high degree of association between these motor outputs. These results are consistent with the view that the neural signal driving the enhanced limb tremor in PD is propagated throughout the motor system, consequently emerging within the postural sway dynamics. This commonality of motor output may be a contributing factor in the differential pattern in the dynamics of effector signal structure in PD as a function of task.     

Classification of macular and optic nerve disease by principal component analysis

In this study, pattern electroretinography (PERG) signals were obtained by electrophysiological testing devices from 70 subjects. The group consisted of optic nerve and macular diseases subjects. Characterization and interpretation of the physiological PERG signal was done by principal component analysis (PCA). While the first principal component of data matrix acquired from optic nerve patients represents 67.24% of total variance, the first principal component of the macular patients data matrix represents 76.81% of total variance. The basic differences between the two patient groups were obtained with first principal component, obviously. In addition, the graphic of second principal component vs. first principal component of optic nerve and macular subjects was analyzed. The two patient groups were separated clearly from each other without any hesitation. This research developed an auxiliary system for the interpretation of the PERG signals. The stated results show that the use of PCA of physiological waveforms is presented as a powerful method likely to be incorporated in future medical signal processing.     

Unveiling relevant non-motor Parkinson's disease severity symptoms using a machine learning approach

ObjectiveIs it possible to predict the severity staging of a Parkinson's disease (PD) patient using scores of non-motor symptoms? This is the kickoff question for a machine learning approach to classify two widely known PD severity indexes using individual tests from a broad set of non-motor PD clinical scales only.MethodsThe Hoehn & Yahr index and clinical impression of severity index are global measures of PD severity. They constitute the labels to be assigned in two supervised classification problems using only non-motor symptom tests as predictor variables. Such predictors come from a wide range of PD symptoms, such as cognitive impairment, psychiatric complications, autonomic dysfunction or sleep disturbance. The classification was coupled with a feature subset selection task using an advanced evolutionary algorithm, namely an estimation of distribution algorithm.ResultsResults show how five different classification paradigms using a wrapper feature selection scheme are capable of predicting each of the class variables with estimated accuracy in the range of 72–92%. In addition, classification into the main three severity categories (mild, moderate and severe) was split into dichotomic problems where binary classifiers perform better and select different subsets of non-motor symptoms. The number of jointly selected symptoms throughout the whole process was low, suggesting a link between the selected non-motor symptoms and the general severity of the disease.ConclusionQuantitative results are discussed from a medical point of view, reflecting a clear translation to the clinical manifestations of PD. Moreover, results include a brief panel of non-motor symptoms that could help clinical practitioners to identify patients who are at different stages of the disease from a limited set of symptoms, such as hallucinations, fainting, inability to control body sphincters or believing in unlikely facts.     

Effects of postural threat on walking features of Parkinson's disease patients

This study investigated whether or not gait kinematics among healthy older individuals and Parkinson's disease (PD) patients are influenced by postural threat. Eight healthy older individuals and eight PD patients were examined while walking at self-selected velocities, under three conditions of postural threat: unconstrained floor; constrained floor (19 cm wide); constrained and elevated floor (19 cm wide by 10 cm high). Independent of the surface conditions, due to motor disturbances caused by the PD these patients walked slower, with shorter strides, and spent more time in the double support phase and less time in the swing phase than did their matched controls. Increases in postural threat resulted in altered gait kinematics for all subjects. Specifically, stride length, stride velocity, cadence, and heel contact velocity decreased, and stride duration and double support duration increased relative to increases in postural threat. All gait alterations were the result of participants’ attempts to facilitate locomotion control and maintain stability. The results of this study reveal that width and height constraints effectively perturbed the balance of all of the walking older individuals. The PD patients were able to modulate gait parameters when faced by a postural threat task.     

Quantitative plasma DNA analysis in Parkinson's disease

Parkinson disease (PD) is a neurodegenerative disease resulting from the loss of the dopaminergic neurons from the substantia nigra pars compacta (SNpc). It is characterized by bradykinesia, rigidity, resting tremor and/or postural instability. The diagnosis of PD is essentially clinical and there is no reliable biological marker to assess its progression. Recently, investigations have been performed on the potential use of circulating cell-free deoxyribonucleic acid (DNA) in the plasma for clinical diagnosis, prognosis and monitoring of human diseases. The aim of this work was to assess the role of free DNA as a biological marker of PD. Forty-two patients with PD (19 men, 23 women) and 20 healthy (7 men, 13 women) subjects were enrolled in this study. Mean ± SD plasma DNA concentration in PD patients and control subjects were, respectively, 16,487 ± 16,378 (range: 100–62,034) kilogenomes-equivalents/L and 37,975 ± 17,832 (range: 15,143–78,783) kilogenomes-equivalents/L. There was a significant difference between control and PD groups (p < 0.001). There was no correlation between plasma DNA levels and demographic or clinical parameters in PD patients. Free DNA does not seem to be a reliable marker of PD progression. Further research is warranted to confirm the present results to have some value as biomarkers in other neurodegenerative diseases.     

Feature selection of stabilometric parameters based on principal component analysis

This study addresses the challenge of identifying the features of the Centre of pressure (COP) trajectory that are most sensitive to postural performance, with the aim of avoiding redundancy and allowing a straightforward interpretation of the results. Postural sway in 50 young, healthy subjects was measured by a force platform. Thirty-seven stabilometric parameters were computed from the one-dimensional and two-dimensional COP time series. After normalisation to the relevant biomechanical factors, by means of multiple regression models, a feature selection process was performed based on principal component analysis. Results suggest that COP two-dimensional time series can be primarily characterised by four parameters, describing the size of the COP path over the support surface; the principal sway direction; and the shape and bandwidth of the power spectral density plot. COP one-dimensional time series (antero-posterior (AP) and medio-lateral (ML)) can be characterised by six parameters describing COP dispersion along the AP direction; mean velocity along the ML and AP directions; the contrast between ML and AP regulatory activity; and two parameters describing the spectral characteristics of the COP along the AP direction. On the basis of the results obtained, some guidelines are suggested for the choice of stabilometric parameters to use, with the aim of promoting standardisation in quantitative posturography.     

Use of principal component factor analysis in the detection of carotid artery disease from Doppler ultrasound

Principal component factor analysis, a mathematical feature extraction technique, has been used to analyse the total information contained in the Doppler signal. In this study two patient groups have been investigated, normals and stenoses of less than 50%. The patients have been classified according to angiographic findings (patients with hypertension, migrane, heart disease, etc. havenot been excluded). The results from the principal component analysis technique have been compared with the more familiar A/B ratio based on the maximum frequency enevelope. Of the 25 normal vessel segments 20 were classified as normal by the A/B ratio technique and 22 by the principal component technique, while of the 19 abnormal vessels 13 were classified as abnormal by the A/B technique and 17 by the principal component analysis. Also the principal component analysis of the total Doppler signal was statistically superior to the A/B ratio in separating the two groups examined in this study.     

BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups

Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here.     

Cortical serotonin-S2 receptor binding abnormalities in patients with Alzheimer's disease: comparisons with Parkinson's disease

Reductions in the numbers of binding sites for the serotonergic S2-receptor antagonist, ketanserin, are, as previously reported, evident in Alzheimer's disease. New findings indicate that these sites are not affected in the cortex of patients with Parkinson's disease despite the presence of cognitive impairment. In contrast S1-receptor binding sites were reduced to a small but significant extent in both Alzheimer's and Parkinson's disease with cognitive deficit. The S2-receptor binding loss was not related to the cholinergic deficit (decreased choline acetyltransferase) common to both disorders nor to the presence of cortical senile plaques but did relate to the extent of cortical neurofibrillary tangle formation, evident in Alzheimer's but not generally in Parkinson's disease. These observations suggest that S2- but not S1-receptor binding abnormalities may reflect an important intrinsic cortical involvement specifically associated with the Alzheimer disease process.     

Normal CAG and CCG repeats in the Huntington's disease genes of Parkinson's disease patients

The clinical features of Parkinson's disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington's disease. Therefore, the CAG and CCG repeats in the Huntington's disease gene were investigated in 45 Parkinson's disease patients and compared to 40 control individuals. All of the Parkinson's disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson's disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington's disease gene are not likely to contribute to the pathogenesis of Parkinson's disease. © 1995 Wiley-Liss, Inc.     

Analysis of EIF4G1 in Parkinson's disease among Asians

Sequence analysis of all the exons of EIF4G1 in 96 Asian patients with Parkinson's disease (PD) did not reveal any pathogenic mutations. A novel coding variant (Pro693Ser) in exon 15 (position 2077) was detected in one PD patient but not in 539 control subjects. Analysis of a coding polymorphic variant (rs2178403) in 1330 subjects revealed similar frequency between control subjects (0.638) and PD patients (0.640). EIF4G1 is an uncommon cause of PD in our Asian cohort.     

Mitochondrial DNA sequence analysis of four Alzheimer's and Parkinson's disease patients

The mitochondrial DNA (mtDNA) sequence was determined on 3 patients with Alzheimer's disease (AD) exhibiting AD plus Parkinson's disease (PD) neuropathologic changes and one patient with PD. Patient mtDNA sequences were compared to the standard Cambridge sequence to identify base changes. In the first AD + PD patient, 2 of the 15 nucleotide substitutions may contribute to the neuropathology, a nucleotide pair (np) 4336 transition in the tRNA^Gln gene found 7.4 times more frequently in patients than in controls, and a unique np 721 transition in the 12S rRNA gene which was not found in 70 other patients or 905 controls. In the second AD + PD patient, 27 nucleotide substitutions were detected, including an np 3397 transition in the ND1 gene which converts a conserved methionine to a valine. In the third AD + PD patient, 2 polymorphic base substitutions frequently found at increased frequency in Leber's hereditary optic neuropathy patients were observed, an np 4216 transition in ND1 and an np 13708 transition in ND5 gene. For the PD patient, 2 novel variants were observed among 25 base substitutions, an np 1709 substitution in the 16S rRNA gene and an np 15851 missense mutation in the cytb gene. Further studies will be required to demonstrate a causal role for these base substitutions in neurodegenerative disease. © 1996 Wiley-Liss, Inc.     

Impulse control disorders in Parkinson's disease in a Chinese population

Background: Dopamine agonists have been used as first-line treatments for patients with Parkinson's disease (PD) during its early stage, and several impulse control disorder (ICD) behaviors have been reported to be associated with their use. Objective: To investigate the association between ICD behaviors and the use of agonists in Chinese patients with PD and associated risk factors. Methods: Self-report screening questionnaires were mailed to 400 PD patients treated with anti-parkinsonian drugs in our clinical database and their spouses (served as control group). Those who screened positive for ICD behaviors by questionnaire were further interviewed over the telephone by a movement disorder specialist to confirm the diagnosis. Results: A total of 11 (3.53%) patients were diagnosed with ICD behaviors as follows: lifetime pathological gambling (1, 0.32%); subclinical or clinical hypersexuality (6, 1.92%); binge eating (1, 0.32%); dopamine dysregulation syndrome (2, 0.64%); and compulsive internet browsing (1, 0.32%). ICD behaviors were associated with an increased mean levodopa equivalent daily dosage and alcohol use (p = 0.005 and p = 0.002, respectively). Patients using dopamine agonists were significantly (p = 0.003) more likely to be diagnosed with an ICD (6.3%) as compared to those who were not (0.6%). Conclusion: PD patients who took dopamine agonists were more likely to report ICD behaviors in Chinese PD.     

Association of GST M1 null polymorphism with Parkinson's disease in a Chilean population with a strong Amerindian genetic component

We have studied the association of a null mutation of Glutathione Transferase M1 (GST M1*0/0) with Parkinson's disease (MIM 168600) in a Chilean population with a strong Amerindian genetic component. We determined the genotype in 349 patients with idiopathic Parkinson's disease (174 female and 175 male; 66.84+/-10.7 years of age), and compared that to 611 controls (457 female and 254 male; 62+/-13.4 years of age). A significant association of the null mutation in GST M1 with Parkinson's disease was found (p=0.021), and the association was strongest in the earlier age range. An association of GSTM1*0/0 with Parkinson's disease supports the hypothesis that Glutathione Transferase M1 plays a role in protecting astrocytes against toxic dopamine oxidative metabolism, and most likely by preventing toxic one-electron reduction of aminochrome.     

The human prion gene M129V polymorphism is not associated with idiopathic Parkinson's disease in three distinct populations

Coexistence of prion disease and idiopathic Parkinson's disease (IPD) has been previously described. It remains unclear whether this relationship may reflect the high incidence of IPD or whether both prion and IPD share common pathogenetic mechanisms. For this reason, we investigated the genotype distribution of the M129V polymorphism of the human prion gene for association with IPD (controls: n = 398, IPD cases: n = 400). No association between genotypes in codon 129 and IPD was detected in three distinct populations, suggesting that this PRNP polymorphism has no direct influence on the susceptibility to IPD.     

Cortical structural involvement and cognitive dysfunction in early Parkinson's disease

Magnetic resonance imaging (MRI) studies in early Parkinson's disease (PD) have shown promise in the detection of disease‐related brain changes in the white and deep grey matter. We set out to establish whether intrinsic cortical involvement in early PD can be detected with quantitative MRI. We collected a rich, multi‐modal dataset, including diffusion MRI, T₁ relaxometry and cortical morphometry, in 20 patients with early PD (disease duration, 1.9 ± 0.97 years, Hoehn & Yahr 1–2) and in 19 matched controls. The cortex was reconstructed using FreeSurfer. Data analysis employed linked independent component analysis (ICA), a novel data‐driven technique that allows for data fusion and extraction of multi‐modal components before further analysis. For comparison, we performed standard uni‐modal analysis with a general linear model (GLM). Linked ICA detected multi‐modal cortical changes in early PD (p = 0.015). These comprised fractional anisotropy reduction in dorsolateral prefrontal, cingulate and premotor cortex and the superior parietal lobule, mean diffusivity increase in the mesolimbic, somatosensory and superior parietal cortex, sparse diffusivity decrease in lateral parietal and right prefrontal cortex, and sparse changes to the cortex area. In PD, the amount of cortical dysintegrity correlated with diminished cognitive performance. Importantly, uni‐modal analysis detected no significant group difference on any imaging modality. We detected microstructural cortical pathology in early PD using a data‐driven, multi‐modal approach. This pathology is correlated with diminished cognitive performance. Our results indicate that early degenerative processes leave an MRI signature in the cortex of patients with early PD. The cortical imaging findings are behaviourally meaningful and provide a link between cognitive status and microstructural cortical pathology in patients with early PD.