Severe Parkinson's Disease Patients Research Articles

Comparative study of bilateral putamen for patients with severe Parkinson's disease detected by 1H magnetic resonance spectroscopy.

The diagnosis of Parkinson's disease (PD) is challenging because the clinical symptoms overlap with other neurodegenerative diseases. The discovery of reliable biomarkers is highly expected to facilitate clinical diagnosis. Through the analysis of the 1H magnetic resonance spectroscopy (1H-MRS) in the putamen, the purpose of the study was to discuss the possibility of the difference in metabolite concentrations between the left and right putamen as biomarkers for patients with severe PD. We collected 1H-MRS of unilateral or bilateral putamen from 41 patients and used the independent sample t-test and paired t-test to analyze 4 metabolite concentrations, including choline (Cho), total N-acetyl aspartate (tNAA), total creatine (tCr), and combined glutamate and glutamine; Bonferroni correction was used to correct P values for multiple comparisons. We designed 4 controlled experiments as follows: (I) PD patients versus healthy controls (HCs) in the left putamen; (II) PD patients versus HCs in the right putamen; (III) the left putamen versus the right putamen for PD patients; and (IV) the left putamen versus the right putamen for HCs. No statistically significant differences (P>0.05) were detected among 4 metabolites in the ipsilateral and bilateral putamen for the PD and HCs groups, except for tCr in the left putamen (PD 6.426±0.557, HCs 6.026±0.460, P=0.046) for ipsilateral comparisons. In the bilateral putamen of severe PD patients, there was no statistically significant difference in the 4 metabolites. The difference (P<0.05) in tCr in the left putamen might be a potential biomarker to distinguish HCs from severe patients in clinic. This might provide a reference for the clinical diagnosis and acquisition strategy of 1H-MRS in severe PD.

Nilotinib is reasonably safe and may halt the disease progression in moderately severe Parkinson's disease patients

The primary objective was nilotinib safety and tolerability in moderately severe PD patients, in this phase II study. An exploratory objective is to assess nilotinib effects on motor and non-motor symptoms at baseline, 6, 12 and 15 months. Participants had PD, with a MDS-UPDRS-III motor score 20-40, and MoCA ≥22. 75 participants were randomized 1:1:1 into placebo, 150mg and 300mg nilotinib oral, once daily for 12 months. 88% of participants completed the treatment and there were no drop-outs due to lack of drug tolerability. Niltonib was found to be reasonably safe with no suspected drug related adverse effects. There was no QTc prolongation or myelosuppression. No differences were observed in MDS-UPDRS-I within and between all study groups tested by a single rater. All groups showed a significant decline in MDS-UPDRS-II scores between baseline and 12 months and after washout. All groups slightly improved on MDS-UPDRS-III motor between baseline and 6 months. The placebo and the 300 mg nilotinib groups remained stable at 12 months and after washout but there was a significant improvement in MDS-UPDRS-III score between baseline and 15 months in the 150 mg nilotinib group (-2.82 points, 95% CI, -4.75- -0.89). No significant differences between each visit were observed in MDS-UPDRS-IV. No statistically significant differences in MDS-UPDRS measurements were observed between groups. There were no statistically significant differences in PDQ-39 between groups, but the placebo group significantly deteriorated after 6 months, while the nilotinib groups did not change. In conclusion these exploratory measures show no clinical worsening in MDS-UPDRS in the nilotinib groups compared to the placebo group that worsened after 6 months of treatment. Taken together, our results will guide the future development of a definitive phase III study to evaluate the effects of nilotinib in PD.

Faecal Transplantation, Pro- and Prebiotics in Parkinson's Disease; Hope or Hype?

Faecal microbiome transplantation (FMT) is an attractive technique, because the administration is relatively simple and in general has a mild adverse effect pattern. Moreover, FMT consists of a broad mixture, which could be beneficial, because at this moment it is not known what type of changes in the microbiome are needed. However, except from a few cases no clinical data in Parkinson’s disease (PD) is available yet. There is some indication that FMT might be beneficial in severe constipated PD patients, but the clinical data to support this are very scarce. So, actually there are no good data in the public domain to support FMT at this moment in PD patients. FMT at this moment is a black box with too many unanswered questions, also with respect to safety concerns. Only the administration of species of Lactobacillus and Bifidobacterium over a time period of four to twelve weeks has repeatedly proven to be effective in treating constipation in PD. Also, no solid clinical data are available about the possible effects of probiotic treatment on motor symptoms or progression of PD. Therefore, also probiotic treatments in PD should wait until better clinical data become available, in order to select the right target populations and to have good estimates of the clinical effects to be expected.

Management of Dysphagia in Patients with Parkinson's Disease and Related Disorders.

Various methods of rehabilitation for dysphagia have been suggested through the experience of treating stroke patients. Although most of these patients recover their swallowing function in a short period, dysphagia in Parkinson's disease (PD) and Parkinson-related disorder (PRD) degenerates with disease progression. Muscle rigidity and bradykinesia are recognized as causes of swallowing dysfunction, and it is difficult to easily apply the strategies for stroke to the rehabilitation of dysphagia in PD patients. Disease severity, weight loss, drooling, and dementia are important clinical predictors. Silent aspiration is a pathognomonic sign that may lead to aspiration pneumonia. Severe PD patients need routine video fluoroscopy or video endoscopy to adjust their food and liquid consistency. Patients with PRD experience rapid progression of swallowing dysfunction. Nutrition combined with nasogastric tube feeding or percutaneous endoscopic gastrostomy feeding should be considered owing to the increased risk of aspiration and difficulty administrating oral nutrition.

Cortical thinning across Parkinson's disease stages and clinical correlates

BackgroundImaging studies have revealed cortical thinning and subcortical atrophy occurring in Parkinson's disease (PD); however, the topographical distribution and clinical associations related to advancing stages of PD remains unclear. ObjectiveWe aimed to investigate the topographical distribution of cortical and subcortical morphometric changes, and their clinical associations, related to increasing disease severity. MethodsIn this cross-sectional imaging study, T1-weighted structural magnetic resonance imaging data for 80 non-demented PD patients and 30 age-matched healthy controls were analysed using FreeSurfer software suite to derive morphometric changes using whole-brain vertex-wise analysis, and surface-based (cortical) and volume-based (subcortical) parcellation maps. PD patients were divided into three groups of mild (n = 27), moderate (n = 27), and severe (n = 26) PD based disease duration and Hoehn and Yahr and Unified Parkinson's Disease Rating Scale Part-III motor severity scores. ResultsWhole-brain vertex-wise analysis revealed cortical thinning in the orbitofrontal cortex in early PD (P = .011), and in the superior frontal (P = .002), caudal middle frontal gyrus (P = .001) and inferior parietal cortex (P = .006) in moderate PD. Severe PD patients showed additional cortical thinning in temporal and occipital cortices (P < .005). Subcortical volume loss was detected in the thalamus (P = .012) and hippocampus (P = .032) in moderate PD, which extended to the caudate (P = .012), putamen (P = .042) and amygdala (P = .008) in severe PD. Increasing disease duration and motor severity scores, correlated with cortical thinning in frontal, temporal, parietal and occipital cortices, and subcortical volumetric loss in the thalamus, caudate, putamen, amygdala and hippocampus. Lower global cognitive status, measured with MMSE, correlated with cortical thinning in temporal, parietal, frontal and cingulate cortices, and with volumetric loss in the hippocampus (r = 0.31; P = .009); suggesting subclinical pathogenic changes occur prior to the onset of cognitive impairment. ConclusionIn conclusion, in more severe disease stages PD patients exhibit progressive cortical thinning and subcortical volume loss which could have relevance to the development of cognitive impairment.

MRI appearances of aquaporin and its effect in different brain regions of patients with Parkinson's disease

Objective To investigate MRI appearances of aquaporin(AQP) and its effect in different brain regions of patients with Parkinson's disease(PD). Methods A prospective study was carried out in 33 PD patients(PD group) and 23 gender- and age-matched healthy controls(control group). Clinical data of PD patients were collected.The aquaporin imaging of diffusion-weighted magnetic resonance imaging(MR-DWI) with multiple b-values in different brain regions were performed to detect the apparent diffusion coefficient(AQP-ADC) values of aquaporin.The PD patients were assessed and graded by modified Hoehn-Yahr grading, then the AQP-ADC values of control group, mild PD group, moderate and severe PD group were analyzed using one-way analysis of variance.The correlation analysis was carried out to detect the relationship between AQP-ADC values in different brain regions and Hoehn-Yahr grading of PD patients. Results Compared with control group, mild PD group had significantly higher AQP-ADC values in red nucleus(RN) and globus pallidus(GP) ((0.24±0.04) vs (0.21±0.04), ( 0.21±0.04) vs (0.16±0.04); both P 0.05); and there was also no significant difference in substantianigra(SN), putamen(Pu) and thalamus(THA) among control group, mild PD group and moderate and severe PD group(P>0.05). The correlation analysis showed that there were negative correlations between the AQP-ADC values in RN and GP and Hoehn-Yahr grading(r=-0.479 and -0.395, P 0.05). Conclusion The AQP-ADC values are increased in RN and GP of mild PD patients, and decreased in moderate and severe PD patients, while there is no significant change in SN, Pu and THA of the two groups, suggesting that the expression of AQP in different brain regions may be related to the severity and pathological stage of PD. Key words: Parkinson's disease; Aquaporin; Molecular imaging; Diffusion-weighted magnetic resonance imaging

Cardiovascular Autonomic Dysfunction in Mild and Advanced Parkinson's Disease.

ObjectiveThe purpose of the present study was to investigate cardiovascular autonomic dysfunction in patients with Parkinson’s disease (PD) with mild to severe stages of motor symptoms and to compare cardiovascular autonomic dysfunction between drug-naïve and dopaminergic drug-treated groups.MethodsThis study included 188 PD patients and 25 age-matched healthy controls who underwent head-up tilt-testing, 24-h ambulatory blood pressure (BP) monitoring and 24-h Holter monitoring. Autonomic function test results were evaluated among groups categorized by motor symptom severities (mild vs. moderate vs. severe) and treatment (drug-naïve or dopaminergic drug treatment).ResultsOrthostatic hypotension and supine hypertension were more frequent in patients with PD than in healthy controls. The frequencies of orthostatic hypotension, supine hypertension, nocturnal hypertension and non-dipping were not different among groups. Additionally, no significant differences were detected in supine BP, orthostatic BP change, nighttime BP, nocturnal BP dipping, or heart rate variabilities among groups.ConclusionsCardiovascular autonomic dysfunction is not confined to moderate to severe PD patients, and starts early in the course of the disease in a high proportion of PD patients. In addition, dopaminergic drug treatments do not affect cardiovascular autonomic function.

Reduction of Motor Disorder in 6-OHDA-Induced Severe Parkinsonism Rats by Post Treatment with Granulocyte-Colony Stimulating Factor

Granulocyte-colony stimulating factor (G-CSF) induced regeneration of dopaminergic neurons and improved behavior deficit in moderate Parkinson's disease (PD) model mice. Post treatment of G-CSF in severe PD model has not been addressed. A very severe PD model in rats was induced by a high dose 6-hydroxydopamine (6-OHDA) injected into the right medial forebrain bundle to evaluate therapeutic effects of G-CSF. G-CSF (50 microg/kg/day for five days) was given on the 9th day after the 6-OHDA injection. Rotational behavior was examined on the 9th and 28th days. Rats were killed on the 28th day and survival dopaminergic neurons in the substantia nigra, dopaminergic axons and dopaminergic receptor 2 in the striatum were examined. We, for the first time, demonstrated that post treatment with G-CSF reduced abnormal rotational behavior and increased the lesion to non-lesion ratio of dopaminergic fibers in the striatum, but the treatment promoted neither the increase in survival dopaminergic neurons nor the increase in dopaminergic receptor 2 expression. We conclude that post treatment with G-CSF can reduce the abnormal rotational behavior of severe PD rats primarily through relative increases in dopaminergic fibers of the lesion side in the striatum. Results of our study suggest therapeutic potentials of G-CSF for treating severe PD patients.

A neurocomputational account of cognitive deficits in Parkinson's disease

Parkinson's disease (PD) is caused by the accelerated death of dopamine (DA) producing neurons. Numerous studies documenting cognitive deficits of PD patients have revealed impairments in a variety of tasks related to memory, learning, visuospatial skills, and attention. While there have been several studies documenting cognitive deficits of PD patients, very few computational models have been proposed. In this article, we use the COVIS model of category learning to simulate DA depletion and show that the model suffers from cognitive symptoms similar to those of human participants affected by PD. Specifically, DA depletion in COVIS produced deficits in rule-based categorization, non-linear information-integration categorization, probabilistic classification, rule maintenance, and rule switching. These were observed by simulating results from younger controls, older controls, PD patients, and severe PD patients in five well-known tasks. Differential performance among the different age groups and clinical populations was modeled simply by changing the amount of DA available in the model. This suggests that COVIS may not only be an adequate model of the simulated tasks and phenomena but also more generally of the role of DA in these tasks and phenomena.

Prevalence of Problem and Pathological Gambling in Parkinson’s Disease

Pathological gambling (PG) has been identified in patients with Parkinson's disease (PD) treated with dopamine agonists suggesting that dysregulation of brain dopaminergic activity may contribute to the development of gambling problems. The current study was undertaken to further establish the prevalence of problem and PG in patients with PD, identify any clinical correlates, and determine if psychiatric or substance use co-morbidity contributes to the increased prevalence of problem and PG. A cross-sectional survey of 140 serially recruited moderate to severe PD patients was undertaken utilizing the Canadian Problem Gambling Index, Alcohol Use Disorders Identification Test, Drug Abuse Screening Test, Beck Depression Inventory, Beck Anxiety Inventory, and Mini-Mental State Exam augmented by chart review, completed over an 8 month period. The 12 month prevalence of problem and PG in PD was 9.3% compared to 1.6% in the general population within a comparably aged sample. The increased prevalence of problem and PG in the PD group was related to dopamine agonist use and younger age, but not co-morbidity. Most subjects with problem and PG reported their gambling increased after being diagnosed with PD and starting treatment. The results suggest that brain dopaminergic activity is involved in the underlying neurobiology of problem and PG.

Intraindividual variability in neurocognitive speed: A comparison of Parkinson's disease and normal older adults

We examined whether intraindividual variability of neurocognitive speed, or inconsistency, is greater in stages of Parkinson's disease (PD) as compared to a matched group of normal older adults. Intraindividual variability was assessed using four reaction time (RT) (simple and complex) tasks. We examined three sets of correlates: executive functioning (Stroop (interference index), Trail Making Test (Part B), and Digit Ordering Test), finger tapping speed, and gait speed. The participants were matched on age, sex, and education, and did not differ in global cognitive functioning. There were 50 patients with a clinical diagnosis of idiopathic PD (29 men and 21 women) who ranged from 65 to 84 years ( M = 71.5, S.D. = 4.7) and 48 matched healthy older adults who ranged from 65 to 84 years ( M = 71.5, S.D. = 4.9). Multiple analyses of variance showed that the PD patients were slower on all three complex RT tasks, and more inconsistent than healthy older adults on the most complex (eight-choice) RT task. Individuals with advanced disease had slower neurocognitive speed and more inconsistency than patients with earlier stage PD. Poorer executive functioning was associated with slower neurocognitive performance in healthy older adults, mild PD patients, and especially severe PD patients. Greater inconsistency in speed was related to poorer executive functioning in late stage PD (for the most complex task) and in healthy older adults (for the simplest task), indicating that motor and cognitive domains have functional coupling (i.e., as one becomes compromised so does the other). Intraindividual variability was not correlated with tapping speed and gait speed in any group. Executive functioning and neurocognitive speed may be valid and distinct clinical markers of disease progression in PD.

Influence of pallidal stimulation and levodopa on gait and preparatory postural adjustments in Parkinson's disease.

In order to assess the influence of the bilateral internal globus pallidus (GPi) stimulation on gait and postural instability in Parkinson's disease (PD), we compared gait kinematic parameters and preparatory postural adjustments before and 3 months after stimulation in off- and on-drug conditions for seven patients. Gait kinematic parameters and displacements of centre of pressure (CP) and shoulder computed before a lateral raising task of the leg, were recorded using optoelectric Vicon system. Levodopa (L-dopa) induced a clear benefit for gait velocity (related to an increase of stride length) and also an increase of swing phase duration. GPi stimulation had a limited effect, since the increase of gait velocity was induced by a concomitant increase of stride length and cadence corresponding to a compensatory mechanism. The benefit on swing phase duration was also moderate. Displacements of CP were improved mainly by L-dopa. GPi stimulation and L-dopa had the same beneficial effect on the speed at which the CP was transferred back towards the support side, the ankle velocity, the onset time for ankle displacement, and the decrease of shoulder amplitude towards the support side, which reflects a better postural adjustment phase. This study, based on an objective method, revealed that chronic bilateral GPi stimulation may improve gait and preparatory postural adjustments in severe PD patients with a more limited effect than L-dopa.

The α 2 agonist, clonidine, improves spatial working memory performance in Parkinson's disease

Previous work has shown that the dopaminergic defect in Parkinson's disease is involved, to some extent, in the “frontal”-like impairment in spatial working memory and attentional set-shifting functions. We investigated whether an α 2 agonist, clonidine (0.5 and 2 μg/kg, per os), could alleviate spatial working memory and attentional set-shifting defect in Parkinson's disease patients. We observed that 2 μg/kg clonidine stimulated spatial working memory accuracy, but had no effect on attentional set shifting or visual recognition memory. Clonidine was also effective in stimulating spatial working memory after withdrawal of dopaminergic drugs, and when this was done, its effect was greater in severe Parkinson's disease patients. In contrast, clonidine failed to stimulate visual recognition memory. These results suggest that disrupted activation of α 2 adrenoceptors may contribute to the impairment of spatial working memory in Parkinson's disease.

Reduction of noradrenaline impairs attention and dopamine depletion slows responses in Parkinson's disease.

We investigated the role dopamine and noradrenaline in the modulation of attention in Parkinson's disease (PD) patients. We observed that PD patients with mild and moderate motor disability did not differ in their attentional accuracy in easy tests, but the severe PD group was slightly disrupted in a more arduous test of attention. Attentional accuracy was not affected by withdrawal of dopaminergic drugs in mild or severe PD patients. The movements of severe PD patients were slower, and withdrawal of dopaminergic drugs aggravated motor slowing more in severe PD patients. Clonidine (0.5 and 2 microg/kg) retarded accuracy of performance in the most difficult attention test in mild PD patients, but had no effect in the severe PD group. Clonidine had no effect on movement times. These data suggest that a defect in noradrenaline release may contribute to the impaired accuracy of attention in severe PD patients and that dopamine may be important for maintaining rapid motor responding.