A longitudinal study of tremor frequencies in Parkinson’s disease and essential tremor

ObjectiveThere is evidence that the tremor frequency in essential tremor (ET) decreases with time. Longitudinal studies on the evolution of tremor frequencies in Parkinson’s disease (PD) have so far not been published. Here, we present a longitudinal analysis of tremor frequencies in PD and ET.MethodsWe analyzed the standardized accelerometric and electromyographic tremor recordings of 53 patients with PD and 38 patients with ET who underwent repeated routine tremor recordings between 1991 and 2002.ResultsIn an average follow-up period of 44.9 months in PD and 50.6 months in ET, the average number of tremor recordings was 3.3 in PD and 3.7 in ET. In both disorders, tremor frequencies tended to decrease with time. The average annual decrease of the tremor frequency was 0.09 Hz/year in Parkinsonian rest tremor, 0.08 Hz/year in Parkinsonian postural tremor and 0.12 Hz/year in ET.ConclusionsThe tremor frequency decreases with time in both PD and ET. The similarity of this decrease in PD and ET may point to a common underlying pathophysiological mechanism.SignificanceDecreasing tremor frequencies with time may be functionally important by inducing larger tremor amplitudes due to the low-pass filtering properties of muscles and limbs.     

Progression of motor symptoms in Parkinson’s disease

Parkinson’s disease(PD)is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms-rigidity,bradykinesia and tremor-due to loss of dopaminergic neurons.The motor symptoms of PD become progressively worse as the disease advances.PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others.In recent years,many studies have investigated the progression of the hallmark symptoms over time,and the cardinal motor symptoms have different rates of progression,with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor.The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability.Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms.However,the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability.Further,none of the currently-available therapies can slow or halt the disease progression.Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression.In this article,the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.     

Timed tests of motor function in Parkinson’s disease

IntroductionTimed tests of motor function in Parkinson’s disease (PD) may be useful for the diagnosis of bradykinesia or to monitor disease progression or treatment response. However, normal ranges have not been established.AimTo define normal ranges of hand-tapping and timed walking tests in non-parkinsonian controls and compare with PD patients’ performance.MethodsWe recruited PD patients and age- and gender-matched controls for a prospective community-based incidence study of parkinsonian disorders in North-East Scotland. We counted the times participants tapped between two counters in 30 s. We also timed a 6m get-up-and-go test. We assessed age and gender effects and calculated 95% reference ranges for controls. We compared PD patients with controls.ResultsWe recruited 157 controls and 138 newly diagnosed, untreated PD patients (mean ages 75 and 73). The 95% control reference range for tapping scores with the dominant hand was 18–74 taps. Males and younger participants performed significantly better. PD patients performed less well (mean difference 15 taps, p < 0.001) but only 10% had tapping scores below the control range. The 95% control reference range for the get-up-and-go test was 9–27 s. Walking times increased significantly with age, but gender had no effect. PD patients were slower (median difference 4.5s, p < 0.001) but only 17% were slower than the control range.DiscussionAlthough PD patients performed more slowly than matched controls, timed tests were not helpful diagnostically because few incident patients were outside the normal reference ranges. Further work is needed on their utility in monitoring disease progression.     

REM sleep behavior disorder and motor dysfunction in Parkinson's disease – A longitudinal study

ObjectivesLongitudinal assessment of a Parkinson's disease (PD) cohort, to investigate the evolution or REM sleep behavior symptoms (RBD) over time and to test the relation between RBD at onset and motor dysfunction progression.MethodsAn early stage PD cohort (n = 61) was assessed at two time points, separated by a two years interval. Diagnostic criteria for RBD were: violent behavior during sleep and body movements or vocalization indicative of dream enacting and at least six affirmative answers in the REM sleep behavior disorder screening questionnaire. Motor function assessment was performed with the Unified Parkinson's Disease Scale part II and III (total and partial scores for tremor, bradykinesia, rigidity, gait/postural instability and dysarthria).Results25 Patients had RBD at baseline, vs. 35 at follow-up. Three RBD changed to non-RBD at follow-up, while 10 non-RBD patients developed RBD at follow-up (annual incidence of 12.5%). RBD and non-RBD patients did not differ significantly at baseline or follow-up. The presence of RBD at baseline was significantly related to an increase in UPDRS total and bradykinesia scores over time.DiscussionRBD symptoms can vary over time and have a tendency to increase during the early stages of disease. The presence of RBD symptoms could be a risk factor for motor function deterioration and particularly for bradykinesia worsening.     

Low-frequency repetitive transcranial magnetic stimulation for dyskinesia and motor performance in Parkinson’s disease

Dyskinesias are one of the most frequent and disabling complications of the long-term treatment of Parkinson’s disease (PD). Although the cause is not completely understood, it appears that an imbalance between excitatory and inhibitory inputs from the basal ganglia to the motor cortex leads to overactivation of motor and premotor areas. Overactivation of the supplementary motor area (SMA) has been observed in neuroimaging studies in dyskinetic PD patients. We investigated the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) of the SMA on levodopa-induced dyskinesias (LID) and motor performance in PD. We tested whether longer duration (10 days) and higher number of total pulses (1800 pulses) would enhance the beneficial effect. Seventeen dyskinetic PD patients were randomly assigned to real rTMS or sham (placebo) rTMS, and 1 Hz rTMS or sham rTMS was applied over the SMA for 10 consecutive days. Patients were assessed at baseline and 1 day after the last rTMS with a levodopa challenge test, and video recordings were taken. Dyskinesias and motor performance were rated off-line by two blinded raters using video recordings. After 10 days of treatment with rTMS, we observed that 1 Hz rTMS delivered over the SMA had decreased LID lasting for 24 hours without a change in motor performance, whereas sham rTMS induced no significant change in dyskinesia scores. These results support a possible therapeutic effect of low-frequency rTMS in LID. However, in order to suggest rTMS as an effective treatment, long-term observations and further investigations with a larger patient population are essential.     

Characterization of cognitive and motor performance during dual-tasking in healthy older adults and patients with Parkinson’s disease

The primary purpose of this study was to investigate the effect of dual-tasking on cognitive performance and gait parameters in patients with idiopathic Parkinson’s disease (PD) without dementia. The impact of cognitive task complexity on cognition and walking was also examined. Eighteen patients with PD (ages 53–88, 10 women; Hoehn and Yahr stage I-II) and 18 older adults (ages 61–84; 10 women) completed two neuropsychological measures of executive function/attention (the Stroop Test and Wisconsin Card Sorting Test). Cognitive performance and gait parameters related to functional mobility of stride were measured under single (cognitive task only) and dual-task (cognitive task during walking) conditions with different levels of difficulty and different types of stimuli. In addition, dual-task cognitive costs were calculated. Although cognitive performance showed no significant difference between controls and PD patients during single or dual-tasking conditions, only the patients had a decrease in cognitive performance during walking. Gait parameters of patients differed significantly from controls at single and dual-task conditions, indicating that patients gave priority to gait while cognitive performance suffered. Dual-task cognitive costs of patients increased with task complexity, reaching significantly higher values then controls in the arithmetic task, which was correlated with scores on executive function/attention (Stroop Color-Word Page). Baseline motor functioning and task executive/attentional load affect the performance of cognitive tasks of PD patients while walking. These findings provide insight into the functional strategies used by PD patients in the initial phases of the disease to manage dual-task interference.     

Taste performance in Parkinson’s disease

While olfactory deficit is already known to be associated with early-stage Parkinson’s disease (PD), taste perception has not fully clarified so far. In this study, we investigated the taste performance in 61 patients with PD and 66 healthy controls (HC) using the Whole Mouth (WMT) and Taste Strip Tests (TST). In addition, we evaluated their olfactory function by means of the Sniffin’ Sticks Test (SST). TST score was significantly lower in PD patients than in HC (TST score 11.0 ± 2.8 vs. 12.2 ± 2.1; p < 0.018) while WMT showed no difference. The olfactory evaluation confirmed the results reported in the literature with a significant reduction of the SST score in PD patients than in HC (SST score 7.0 ± 2.8 vs. 11.3 ± 2.8; p < 0.0001). The conflicting results revealed by TST and WMT could rely on a taste impairment not detectable at supra-threshold concentration of tastes, typical of the daily life. Possible biological correlates of taste impairment in PD are discussed.     

Exercise improves motor deficits and alters striatal GFAP expression in a 6-OHDA-induced rat model of Parkinson’s disease

Astrocytic changes have been demonstrated in several neurodegenerative diseases, showing that these cells play an important role in functional recovery/maintenance against brain damage. Physical exercise is known to contribute to this process; however, the cellular mechanisms involved are not fully understood. This study investigated the effects of physical exercise on motor deficits and the expression of glial fibrillary acidic protein (GFAP) in a model of Parkinson's disease (PD). Rats were divided into four groups: sham sedentary (SS) and sham trained (ST); lesioned sedentary (LS) and lesioned trained (LT). 6-OHDA was infused unilaterally into the medial forebrain bundle. Behavioral tasks were applied to evaluate motor abilities. Tyrosine hydroxylase (TH-in substantia nigra) and GFAP (in striatum) immunoreactivities (ir) were semi-quantified using optical density. The animals submitted to treadmill training completed fewer pharmacological-induced rotations when compared with sedentary animals and they also showed ameliorated motor impairments. Interestingly, although no change in TH-ir, the exercise led to restored striatal GFAP expression in the LT group while there was no effect in the ST group. This study is the first study to show data indicating the recovery of GFAP expression post-exercise in this model and further research is necessary to determine the precise action mechanisms of exercise on astrocytes in the PD.     

Chronic coffee consumption and striatal DAT-SPECT findings in Parkinson’s disease

Coffee may interfere with the dopaminergic transmission, and this action would possibly enhance motor activity and exert an antidyskinetic effect in Parkinson’s disease (PD). This study aimed to see whether coffee habit could be associated with change in striatal dopamine active transporter (DAT)-single photon emission computed tomography (SPECT) imaging in PD. A total of 83 PD patients (71 current coffee drinkers and 12 never drinkers) underwent a DAT-SPECT study, using [123I]FP-CIT as radionuclide. Socio-demographic and clinical information as well as smoking habit was collected at the time of imaging acquisition. The Unified Parkinson’s Disease Rating Scale part III was used to evaluate disease severity. On multivariable analysis, chronic coffee consumption was not associated with any significant change in striatal uptake of the radionuclide. However, the number of years patients drunk coffee was correlated with a significant increase in age at PD onset (p?<?0.001). Confirming a previous report, current cigarette smoking was associated with a reduction of radionuclide uptake in putamen and caudate (p?<?0.001).     

Cardiovascular variability in Parkinson’s disease and extrapyramidal motor slowing

Objective

Parkinson’s disease (PD) is a degenerative neurological condition, associated with cardiovascular dysfunction. Many studies have utilised heart rate variability (HRV) to assess the autonomic nervous system in PD, but blood pressure variability (BPV) has received less attention. The purpose of the present study was to compare HRV and BPV between participants with established PD, extrapyramidal motor slowing (EPMS) (not reaching clinical criteria for PD), older healthy controls (OHC), and young healthy controls (YHC), in order to ascertain whether either of these measures can be used as an early marker of non-motor symptoms in PD.

Methods

HRV was assessed at rest and during 2?min of slow deep breathing in 97 participants, divided into four groups: YHC (20–30?years; n?=?19); OHC (67–83?years; n?=?28); EPMS (59–91?years; n?=?25) and PD (61–84?years; n?=?25).

Results

Spectral analysis of blood pressure was performed on stable non-invasive recordings of blood pressure obtained in 76 of the participants. Low frequency (LF) and high frequency (HF) components, and the LF/HF ratio, were measured. Significant differences were only seen between the YHC and the three older groups. For HRV this was seen at rest and during 2?min of slow deep breathing, whereas for BPV this was only seen during 2?min of slow deep breathing.

Interpretation

These data indicate that there are only age-related changes in HRV and BPV, and that neither technique is sensitive enough to provide an index of pre-clinical PD.     

Progression of sleep disturbances in Parkinson’s disease: a 5-year longitudinal study

Journal of Neurology - Sleep disorders can occur in early Parkinson’s disease (PD). However, the relationship between different sleep disturbances and their longitudinal evolution has not...     

Brain network topology and future development of freezing of gait in Parkinson’s disease: a longitudinal study

Journal of Neurology - Freezing of gait (FOG) is a common disabling gait disturbance in Parkinson’s disease (PD). The objectives of this study were to explore alterations in the topological...     

Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson’s disease

We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson’s disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson’s disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (±standard deviation) improvement in Unified Parkinson’s Disease Rating Scale part III was 37 ± 11%, mean daily “off” period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily “on” time increased from 10.2 ± 3 to 13.7 ± 2 hours, “on” period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson’s Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily “on” period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.     

Effects of rTMS on Parkinson’s disease: a longitudinal fMRI study

Parkinson’s disease is a movement disorder whose principal symptoms are tremor, rigidity, bradykinesia and postural instability. Initially, drugs like l-dopa or dopaminergic agonists are able to control these symptoms, but with the progress of the disease these drugs become less effective. Previous studies have reported that repetitive transcranial magnetic stimulation (rTMS) can improve these motor symptoms. The objective of this study was to investigate the neural mechanisms through which 25 Hz rTMS may improve motor symptoms in Parkinson’s disease. In a double-blind placebo-controlled study, we evaluated the effects of 25 Hz. rTMS in 10 Parkinson’s disease patients. Fifteen rTMS sessions were performed over the primary cortex on both hemispheres (one after the other) during a 12-week period. The patients were studied using functional magnetic resonance imaging during performance of a simple tapping and a complex tapping task, 1 week before the administration of the first rTMS session and just after the last session. rTMS improved bradykinesia, while functional magnetic resonance imaging showed different cortical patterns in prefrontal cortex when patients performed the complex tapping test. Furthermore, the improvement in bradykinesia is associated with caudate nucleus activity increases in simple tapping. Finally, we observed a relative change in functional connectivity between the prefrontal areas and the supplementary motor area after rTMS. These results show a potential beneficial effect of repetitive transcranial magnetic stimulation on bradykinesia in Parkinson’s disease which is substantiated by neural changes observed in functional magnetic resonance imaging.     

Changes in the solubility and phosphorylation of ��-synuclein over the course of Parkinson��s disease

Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson's disease in regions affected early through to end-stage disease. Brain tissue samples from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks. 500 mg of frozen putamen (affected preclinically) and frontal cortex (affected late) was homogenized, fractionated and α-synuclein levels evaluated using specific antibodies (syn-1, BD Transduction Laboratories; S129P phospho-α-synuclein, Elan Pharmaceuticals) and quantitative western blotting. Statistical analyses assessed the relationship between the different forms of α-synuclein, compared levels between groups, and determined any changes over the disease course. Soluble S129P was detected in controls with higher levels in putamen compared with frontal cortex. In contrast, insoluble α-synuclein occurred in Parkinson's disease with a significant increase in soluble and lipid-associated S129P, and a decrease in soluble frontal α-synuclein over the disease course. Increasing soluble S129P in the putamen correlated with increasing S129P in other fractions and regions. These data show that soluble non-phosphorylated α-synuclein decreases over the course of Parkinson's disease, becoming increasingly phosphorylated and insoluble. The finding that S129P α-synuclein normally occurs in vulnerable brain regions, and in Parkinson's disease has the strongest relationships to the pathogenic forms of α-synuclein in other brain regions, suggests a propagating role for putamenal phospho-α-synuclein in disease pathogenesis.     

How do cognitive and axial motor signs correlate in Parkinson’s disease? A 6-year prospective study

Impairment of Parkinson’s disease (PD) axial motor signs (AMS) has been described as a risk factor for dementia. Executive dysfunction is an important feature in recently proposed clinical diagnostic criteria for PD dementia. To clarify the relationship between AMS progression and executive cognitive performance, we conducted a 6-year prospective study in PD patients without AMS impairment at baseline. A hospital-based cohort of PD patients (n = 24) without dementia, in the initial motor stage (Hoehn–Yahr ≤ 2), and matched controls (n = 20) were followed prospectively over a 6-year period. Neuropsychological tests were performed in both groups, and motor function (including AMS: speech, gait, postural instability) was evaluated in the PD group. The PD group had a significantly higher decline in neuropsychological test scores than did the controls. Most of the neuropsychological and motor decline occurred in the last 4 years. In UPDRS III, progression of AMS and especially speech were the most important motor variables related to dementia. There was a correlation between speech impairment progression and declines in MMSE (r = −0.598, p = 0.002), Clock Drawing (r = −0.671, p < 0.001), Semantic Verbal Fluency (r = −0.435, p = 0.034), Alternating Sequences (r = 0.497, p = 0.014), and Raven’s Coloured Progressive Matrices (r = −0.735, p < 0.001). PD patients with higher speech impairment progression showed more rapid declines in some neuropsychological tests. Further studies are needed to clarify the different roles of speech, gait and postural instability on the initial phases of cognitive dysfunction.