Parkinsonian Individuals Research Articles

Cardiac Changes in Parkinson's Disease: Lessons from Clinical and Experimental Evidence.

Dysautonomia is a common non-motor symptom in Parkinson’s disease (PD). Most dysautonomic symptoms appear due to alterations in the peripheral nerves of the autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. The degeneration of sympathetic nerve fibers and neurons leads to cardiovascular dysfunction, which is highly prevalent in PD patients. Cardiac alterations such as orthostatic hypotension, heart rate variability, modifications in cardiogram parameters and baroreflex dysfunction can appear in both the early and late stages of PD, worsening as the disease progresses. In PD patients it is generally found that parasympathetic activity is decreased, while sympathetic activity is increased. This situation gives rise to an imbalance of both tonicities which might, in turn, promote a higher risk of cardiac damage through tachycardia and vasoconstriction. Cardiovascular abnormalities can also appear as a side effect of PD treatment: L-DOPA can decrease blood pressure and aggravate orthostatic hypotension as a result of a negative inotropic effect on the heart. This unwanted side effect limits the therapeutic use of L-DOPA in geriatric patients with PD and can contribute to the number of hospital admissions. Therefore, it is essential to define the cardiac features related to PD for the monitorization of the heart condition in parkinsonian individuals. This information can allow the application of intervention strategies to improve the course of the disease and the proposition of new alternatives for its treatment to eliminate or reverse the motor and non-motor symptoms, especially in geriatric patients.

Effect of reading passage length on quantitative acoustic speech assessment in Czech-speaking individuals with Parkinson's disease treated with subthalamic nucleus deep brain stimulation.

Little is known about the minimum sample length required for the stable acoustic assessment of speech in Parkinson's disease (PD). This study aimed to investigate the effect of the duration of the reading passage on the determination of reliable acoustic patterns in individuals with PD treated with subthalamic nucleus deep brain stimulation. A phonetically balanced reading text of 313 words was collected from 32 Czech persons with PD, and 32 age- and sex-matched healthy controls. The reading passage was segmented to produce ten sub-texts of increasing length ranging from a one- to a ten-segment-long sub-text. An error rate analysis was used to estimate the required stabilization value by evaluating the differences between the sub-texts and the entire text across seven hypokinetic dysarthria features. The minimum length of a reading passage equal to 128 words was found to be necessary for acoustic assessment, with similar lengths being required for the controls (120 words) and the two PD subgroups, including Parkinsonian individuals with a mild (126 words) and moderate (128 words) dysarthria severity. The current study provides important guidelines for the necessary sample length for future expert instrumental dysarthria assessments and assists in decreasing the time required for clinical speech evaluations.

A Randomized, Controlled Trial of Exercise for Parkinsonian Individuals With Freezing of Gait.

Exercises with motor complexity induce neuroplasticity in individuals with Parkinson's disease (PD), but its effects on freezing of gait are unknown. The objective of this study was to verify if adapted resistance training with instability - exercises with motor complexity will be more effective than traditional motor rehabilitation - exercises without motor complexity in improving freezing-of-gait severity, outcomes linked to freezing of gait, and brain function. Freezers were randomized either to the adapted resistance training with instability group (n = 17) or to the active control group (traditional motor rehabilitation, n = 15). Both training groups performed exercises 3 times a week for 12 weeks. The primary outcome was the New Freezing of Gait Questionnaire. Secondary outcomes were freezing of gait ratio (turning task), cognitive inhibition (Stroop-III test), motor signs (Unified Parkinson's Disease Rating Scale part-III [UPDRS-III]), quality of life (PD Questionnaire 39), anticipatory postural adjustment (leg-lifting task) and brain activation during a functional magnetic resonance imaging protocol of simulated anticipatory postural adjustment task. Outcomes were evaluated before and after interventions. Only adapted resistance training with instability improved all the outcomes (P < 0.05). Adapted resistance training with instability was more effective than traditional motor rehabilitation (in improving freezing-of-gait ratio, motor signs, quality of life, anticipatory postural adjustment amplitude, and brain activation; P < 0.05). Our results are clinically relevant because improvement in the New Freezing of Gait Questionnaire (-4.4 points) and UPDRS-III (-7.4 points) scores exceeded the minimally detectable change (traditional motor rehabilitation group data) and the moderate clinically important difference suggested for PD, respectively. The changes in mesencephalic locomotor region activation and in anticipatory postural adjustment amplitude explained the changes in New Freezing of Gait Questionnaire scores and in freezing-of-gait ratio following adapted resistance training with instability, respectively. Adapted resistance training with instability is able to cause significant clinical improvement and brain plasticity in freezers. © 2020 International Parkinson and Movement Disorder Society.

Loss of presynaptic inhibition for step initiation in parkinsonian individuals with freezing of gait

Individuals with freezing of gait (FoG) due to Parkinson's disease (PD) have small and long anticipatory postural adjustments (APAs) associated with delayed step initiation. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs due to supraspinal dysfunction. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, it may be deficient in freezers during APAs. We show that freezers presented PSI in quiet stance (control task), but they presented loss of PSI (i.e. higher ratio of the conditioned H-reflex relative to the test H-reflex) during APAs before step initiation (functional task), whereas non-freezers and healthy control individuals presented PSI in both the tasks. The loss of PSI in freezers was associated with both small APA amplitudes and FoG severity. We hypothesize that loss of PSI during APAs for step initiation in freezers may be due to FoG. Freezing of gait (FoG) in Parkinson's disease involves deficient anticipatory postural adjustments (APAs), resulting in a cessation of step initiation due to supraspinal dysfunction. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, here we hypothesized a loss of PSI in freezers during APA for step initiation, which would be associated with FoG severity. Seventy individuals [27 freezers, 22 non-freezers, and 21 age-matched healthy controls (HC)] performed a 'GO'-commanded step initiation task on a force platform under three conditions: (1) without electrical stimulation, (2) test Hoffman reflex (H-reflex) and (3) conditioned H-reflex. They also performed a control task (quiet stance). In the step initiation task, the H-reflexes were evoked on the soleus muscle when the amplitude of the APA exceeded 10-20% of the mean baseline mediolateral force. PSI was quantified by the ratio of the conditioned H-reflex relative to the test H-reflex in both the tasks. Objective assessment of FoG severity (FoG-ratio) was performed. Freezers presented lower PSI levels during quiet stance than non-freezers and HC (P<0.05). During step initiation, freezers presented loss of PSI and lower APA amplitudes than non-freezers and HC (P<0.05). Significant correlations were only found for freezers between loss of PSI and FoG-ratio (r=0.59, P=0.0005) and loss of PSI and APA amplitude (r=-0.35, P<0.036). Our findings suggest that loss of PSI for step initiation in freezers may be due to FoG.

Non-contact measurement of tremor for the characterisation of Parkinsonian individuals: comparison between Kinect and Laser Doppler vibrometer

Parkinson’s disease is a progressive neurodegenerative disorder affecting the central nervous system. One of its main and most evident symptoms is the tremor, which usually manifests at rest with varying intensity during time. An important diagnostic challenge is the differential diagnosis between Parkinson’s disease and the other most widely represented tremor syndrome, i.e. Essential (or senile) tremor. At present there are no standard methods for the quantification of tremor and the diagnosis of both Parkinson’s disease and Essential tremor is mainly done on the base of clinical criteria and by using rating scales. The aim of this work is to objectively and non-invasively assess the tremor linked to the quoted diseases, using non-contact techniques: Laser Doppler Vibrometer (LDV) and Kinect for Windows device. Two subjects with Parkinson’s disease and one with Essential tremor were tested in different conditions: at rest, during a cognitive task, with forward stretched arms and in “Wing position”. The results from data processing in terms of tremor frequency seem to be comparable, with a mean deviation of 0.31 Hz. Furthermore, the values computed are consistent with what is stated in the literature (i.e. 4-12 Hz). So, both LDV and Kinect device can be considered suitable to be used as an objective means for the assessment and monitoring of Parkinson’s disease tremor, helping the clinician in the choice of the most suitable treatment for the patients.

Gaucher disease ascertained through a Parkinson's center: Imaging and clinical characterization

Among the genes implicated for parkinsonism is glucocerebrosidase (GBA), which causes Gaucher disease (GD). Despite a growing literature that GD may present as parkinsonism, neuroimaging, olfaction, and neuropsychological testing have not been extensively reported. We describe transcranial sonography (TCS), 18F-fluorodopa (F-dopa) and fluorodeoxyglucose (FDG) Positron emission tomography, olfaction testing, neuropsychological testing, and clinical features in homozygous and compound heterozygous GBA mutation carriers identified through screening of 250 Ashkenazi Jewish parkinsonian individuals treated at a tertiary care center. We identified two individuals with N370S/R496H compound heterozygous mutations and two with N370S homozygous mutations; one individual died before completing detailed evaluation. TCS (n = 3) demonstrated nigral hyperechogenicity that was greater than controls [median area maximal substantia nigra echogenicity (aSNmax) = 0.28 cm(2) vs. 0.14 cm(2), P = 0.005], but similar to idiopathic PD (aSNmax = 0.31 cm(2)). FDG PET (n = 2) demonstrated hypermetabolism of the lentiform nuclei, and F-fluorodopa PET (n = 2), bilateral reduction in striatal F-dopa uptake. Olfaction was markedly impaired in the two tested cases, including onset of smell disturbance in adolescence in one. Neuropsychological features (n = 3) were consistent with Parkinson's disease (PD) or diffuse Lewy body disease (DLB). The imaging, neuropsychological and olfactory markers suggest the GD phenotype includes PD with and without features of DLB, marked olfactory loss, nigral hyperechogenicity on TCS, and F-dopa and FDG PET abnormalities.

Choice reaction time after levodopa challenge in parkinsonian patients

Various types of choice reaction time paradigms demonstrated deficits in the preparation and execution of movements in parkinsonian subjects. These studies showed controversial results, since they included parkinsonian individuals being: (i) previously untreated; (ii) off; or (iii) on anti-parkinsonian medication. Moreover, these trials do not take into consideration the acute effects of levodopa administration. Objective of this study was to determine the effect of long-term dopaminergic substitution therapy within a standardized levodopa challenge test in combination with a repeatedly performed choice reaction time task in parkinsonian individuals. Parkinsonian participants consisted of previously untreated, so-called “de-novo” patients and of individuals, who were chronically substituted with dopaminergic drugs, but were taken off medication for at least 12 h. All participants took 250 mg levodopa/benserazide after assessment of baseline data. Then we repeatedly measured choice reaction- and movement time within the next 90 min. No significant change of the assessed task data appeared in the “de-novo” group, but reaction- and movement time significantly shortened in previously treated subjects. Sedative effects of levodopa and/or dopaminergic overstimulation hypothetically explain the results of the previously untreated patients, whereas long-term dopaminergic substitution therapy hypothetically causes tolerance to these phenomena in treated parkinsonian individuals. Future studies on parkinsonian subjects should discuss their results on the basic pathophysiology or basal ganglia dysfunction in the light of a putative impact of long-term anti-parkinsonian drug therapy.

PCR Analysis of platelet mtDNA: Lack of specific changes in Parkinson's disease

An alteration within the mitochondrial DNA (mtDNA) has been hypothesized to underlie the deficiencies in mitochondrial complex I activity observed in the platelets, striatal muscle, and brain tissue of individuals with Parkinson's disease. Here we utilized the polymerase chain reaction (PCR) to analyze mtDNA obtained from the platelets of nonmedicated patients with early Parkinson's disease (n = 8) and aged-matched controls (n = 6) for the presence of deletion(s) or addition(s) equal to or greater than 50-100 base pairs. Initial attention was focused upon detecting a 4.977 kb deletion previously found in the brains of parkinsonian patients and some aged controls. Indeed, a large deletion of approximately 5.0 kb was observed in the platelet mtDNA from all parkinsonian individuals. However, this defect was also found in all age-matched controls as well as in a group of young healthy subjects (n = 5). In addition, we searched for the presence of smaller changes in platelet mtDNA from parkinsonian patients by PCR analysis of four mtDNA segments that code for seven of the complex I polypeptides. No large deletions or additions were detected within these four regions of mtDNA in any of the disease or age-matched control samples. We conclude that (a) a 4.977 kb deletion is apparently present in a subpopulation of platelet mtDNA from all individuals, and (b) no macrosequence alteration in mtDNA is likely to underlie the deficiency in complex I activity reported in platelet mitochondria from parkinsonian patients.

Reaction time and nigrostriatal dopamine function: the effects of age and practice

Normal aged and Parkinsonian individuals lose the ability to initiate movements rapidly (increased reaction time) in parallel with changes in the nigrostriatal dopamine (DA) system. However, the ability of these individuals to improve their reaction time with practice has not been adequately assessed. We have developed a rodent model for human reaction time in which reaction time performance correlates highly with neurochemical measures of nigrostriatal DA integrity. In the present report, 15 young and 10 old male Sprague-Dawley rats were conditioned in a reaction time task to release a lever quickly in response to external stimuli in order to avoid a mild footshock. In order to examine the effects of practice on this reaction time task, the young animals were tested for 5 days at 3, 6 and 9 months of age and the old animals were tested for 5 days at 18, 21, and 24 months of age. From this well-practiced task, reaction time response latencies were measured and compared to measures of nigrostriatal DA function (steady-state levels of DA and its metabolites, D 2 DA receptor affinity and density). The old animals were slower in response latencies than the young animals. These age differences in response latencies, however, disappeared after several days of testing at each of the 3 test sessions, so that the old animals were not significantly slower than the young animals on days 4 and 5 of each session. As expected, the old animals showed reduced striatal D 2 DA receptor density with no age differences in DA receptor affinity. The old animals had significantly higher ratios of DA metabolities (dihydroxyphenylacetic acid and homovanillic acid; DOPAC + HVA) to DA than the young animals. Furthermore, across groups there was a significant negative correlation between striatal D 2 DA receptor numbers and response latencies. This negative correlation indicated that the animals with the faster (lower) response latencies had the higher number of striatal D 2 DA receptors. These data suggest that the plasticity of the motor system allows age-related impairments in reaction time to be overcome with extensive practice. It also appears that reaction time is related to multiple aspects of nigrostriatal DA function.