Disturbances In Parkinson's Disease Research Articles

A novel method improving motor disturbance in Parkinson disease: Application of glycerin poultice to the flexor digitorum profundus in the middle phalanx of the little finger

To investigate whether the application of glycerin poultice to the flexor digitorum profundus in the middle phalanx of the little finger (GFML) improves motor disturbance in Parkinson Disease (PD). Dorsiflexion of the little finger and diameter of the pupil in 22 patients with PD and 23 control subjects was evaluated before and after application of GFML. Motor disturbance in patients with PD was evaluated before and after application of GFML. The application of GFML increased dorsiflexion of the little finger and constricted the pupil in all subjects, which suggests that application of GFML caused the decreased tension of the flexor digitorum profundus and lowered sympathetic nerve activity. With application of GFML, motor disturbance in patients with PD was improved. The application of GFML improves motor disturbance in PD which might be caused by reversing the mechanism of the muscle mechanosensitive reflex.

Hallucinations, Dreaming, and Frequent Dozing in Parkinson Disease: Impact of Right-hemisphere Neural Networks

To relate sleep disturbances in Parkinson disease (PD) to hemispheric asymmetry of initial presentation. Sleep disturbances are common in PD arising from the neurodegenerative process underlying the disease, which is usually lateralized at onset. Patients with left-side Parkinson disease onset (LPD: right hemisphere dysfunction) exhibit reduced vigilance relative to those with right-side Parkinson disease onset (RPD: left hemisphere dysfunction), leading us to hypothesize that sleep-related disturbances, particularly excessive daytime sleepiness, would be more severe for LPD than for RPD. Thirty-one nondemented participants with PD (17 RPD and 14 LPD) and 17 age-matched control (CO) participants with chronic health conditions were administered the Parkinson Disease Sleep Scale and polysomnography was performed on a subset of the PD participants. Both PD subgroups exhibited more nighttime motor symptoms than the CO group, but only LPD endorsed more nocturnal hallucinations and daytime dozing. Controlling for mood additionally revealed more vivid dreaming in LPD than RPD. There were no significant differences between LPD and RPD on measures of sleep architecture. Increased dreaming, hallucinations, and daytime somnolescence in LPD may be related to changes in right-hemisphere neural networks implicated in the generation and control of visual images, arousal, and vigilance. Our results underscore the need to consider side of onset in regard to sleep disturbances in PD.

Pupillary supersensitivity and visual disturbance in Parkinson’s disease

This study evaluated pupillary postganglionic autonomic dysfunction and its relationship to visual disturbance in idiopathic Parkinson's disease (PD). Pupillary sensitivity was examined in relation to a parasympathomimetic agent [0.05% pilocarpine hydrochloride (PL)] and to a sympathomimetic agent [0.02% dipivefrine hydrochloride (DPE)] using infrared pupillography in 40 PD patients and 17 age-matched controls. Visual disturbances were evaluated as well, including blurring, photophobia, night blindness and involuntary eyelid closure in response to light. Pupillary supersensitivity to PL and DPE and their relation to visual disturbances were found to be significantly greater in PD patients than in controls (22.3 +/- 15.1 vs. 10.4 +/- 11.4%, P < 0.005, and14.5 +/- 14.5 vs. 4.9 +/- 8.7%, P < 0.01, respectively). In addition, pupillary sympathetic supersensitivity did not correlate with a reduction of 123I-metaiodobenzylguanidine (MIBG) cardiac accumulation. Patients with PD reported more blurred vision (P < 0.001) and involuntary eyelid closure in response to light (P < 0.05) than controls. Patients with supersensitivity to both PL and DPE complained more often of blurred vision than patients without supersensitivity (P < 0.05). Pupillary sensitivity to PL correlated significantly with a summed score for visual disturbance (P < 0.05, r = 0.417), but DPE sensitivity did not. PD patients have both parasympathetic and sympathetic postganglionic impairments affecting the pupil. Our findings demonstrate that parasympathetic dysfunction contributes significantly to visual disturbance in PD.

Cognitive and behavioural impairment in Parkinson's disease

Although Parkinson's disease (PD) has been considered to primarily affect motor abilities, increasing emphasis is being placed on cognitive and behavioural impairment in this disorder. Depression, dementia, psychosis and impulse control disorders have a major impact on quality of life for both patients and families. This article reviews cognitive and behavioural disturbances in PD and their relation to affective and motor symptoms, treatment of dementia associated with PD, and treatment approaches to psychosis in PD. We also discuss similarities between the dementia of PD and dementia with Lewy bodies.

Preferential loss of serotonin markers in caudate versus putamen in Parkinson's disease

Interest in serotonergic involvement in Parkinson's disease (PD) has focussed recently on the possibility that the remaining serotonin neurons innervating striatum (caudate and putamen) might release dopamine as a 'false transmitter'--an action that could have both beneficial and harmful (e.g. promotion of levodopa-induced dyskinesias) consequences. Evidence for a brain serotonergic disturbance in PD is derived in large part from findings of decreased binding of different radioligands to the serotonin transporter (SERT), one 'marker' of serotonin neurons. However, it is not known whether the reported changes in SERT binding reflect actual changes in levels of SERT protein or whether concentrations of all serotonin markers are similarly and markedly decreased in the two striatal subdivisions. We measured levels of SERT immunoreactivity, and for comparison, protein levels of tryptophan hydroxylase (TPH; the marker synthetic enzyme) using a Western blot procedure, as well as concentrations of serotonin, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and dopamine by HPLC in post-mortem striatum of patients with PD and normal controls. Whereas concentrations of dopamine were severely decreased (caudate, -80%; putamen, -98%) and showed little (caudate) or no (putamen) overlap between individual control and patient values, levels of all four serotonin markers were less markedly reduced (-30% to -66%) with some patients having distinctly normal levels. Unlike the preferential loss of dopamine in putamen, the caudate was affected more than putamen by loss of all serotonin markers: serotonin (-66% versus -51%), 5-HIAA (-42% versus -31%), SERT (-56% versus -30%) and TPH (-59% versus -32%). Striatal serotonin concentration was similar in the subset of patients reported to have had dyskinesias versus those not reported to have had this drug complication. Previous findings of decreased SERT binding are likely explained by loss of SERT protein. Reduced striatal levels of all of the key serotonergic markers (neurotransmitter and metabolite, transporter protein, synthesizing enzyme protein) provide strong evidence for a serotonergic disturbance in PD, but with some patients affected much more than others. The more marked caudate reduction suggests that raphe neurons innervating this area are more susceptible to 'damage' than those innervating putamen and that any functional impairment caused by striatal serotonin loss might primarily involve the caudate. Questions related to the, as yet undetermined, clinical consequences in PD of a striatal serotonin deficiency (caudate: cognitive impairment?) and preservation (putamen: levodopa-induced dyskinesias?) should be addressed in prospective brain imaging and pharmacological studies.

Hypocretin/Orexin: A Molecular Link Between Sleep, Energy Regulation, and Pleasure

Hypocretin (Hcrt) is a neurotransmitter of the dorsal and lateral hypothalamus that regulates sleep, appetite, and energy consumption. Recent evidence indicates that it is also involved in pleasure/reward-seeking. Mutation of the Hcrt-receptor gene causes narcolepsy in canines, and Hcrt knockout mice exhibit narcolepsy-like symptoms. Human narcoleptics do not commonly have mutations in the ligand or receptor but do have degeneration of Hcrt-containing neurons, possibly through an autoimmune mechanism. When Hcrt neurons degenerate in mice, hypophagia and obesity are observed, symptoms that are also present in some human narcoleptics. This article reviews the recent literature with regard to the many functions of this single molecule. The authors suggest that eating habits and impulsivity may be topics worth exploring in the evaluation of narcoleptic patients.

Disturbed surround inhibition in preclinical parkinsonism

Objective Surround inhibition in the motor system is an essential mechanism for selective execution of desired movements. To evaluate the functional operation of surround inhibition in Parkinson disease, we performed a transcranial magnetic stimulation (TMS) study in the asymptomatic hands of hemiparkinsonism patients. Methods TMS was set to be triggered by self-initiated flexion of the index finger at different intervals from 3 to 2000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of control TMS at rest. Normalized MEP amplitudes of the patients’ self-triggered TMS sessions at different intervals were compared to those of the controls. Results During index finger flexion, MEP amplitudes from the little finger muscle were unchanged in normal subjects. However, they were enhanced in Parkinson patients, despite the absence of any motor disturbance. Conclusions These results suggest that the functional operation of surround inhibition is impaired in Parkinson disease. This disturbance may precede motor disturbance in Parkinson disease. Significance Impaired surround inhibition can be useful to detect preclinical parkinsonism.

Characteristics of sleep disturbances in Japanese patients with Parkinson's disease. A study using Parkinson's disease sleep scale

The present multicenter cross-sectional study was performed using semistructured questionnaires to determine the contributing factors of sleep disturbances in Japanese patients with Parkinson's disease (PD). We used the Parkinson's disease sleep scale (PDSS, Japanese version). All data were obtained by means of interviewed questionnaire and physical examination by neurologists. The study was carried out between April 2005 and December 2005 at eight university hospitals and affiliated facilities in the Kanto area of Japan. A total of 188 (85 men and 103 women) PD patients and 144 controls (64 men and 80 women) were included. Stepwise regression analysis identified complications of treatment, depression, age, and disease duration as significant risk factors of sleep disturbances in PD. Significant differences in total PDSS score were observed between Hoehn & Yahr (H&Y) Stages 1 and 4, between H&Y Stages 2 and 4, and between H&Y stages 3 and 4 (Bonferroni test). The results of this survey suggested that complications due to treatment (dyskinesia, wearing off, on-off), depressive state, and disease stage are significant determinants of sleep disorders in Japanese patients with PD. We speculate that the reduction of neurotransmitters involved in the sleep-wakefulness mechanism and degeneration of neurons progress together in parallel with deterioration of motor function.

Sleep disorders in Parkinson's disease: An overview

Sleep disturbances are one of the most common of the nonmotor complications of Parkinson's disease (PD), and increase in frequency with advancing disease. The causes of sleep disturbance in PD are numerous, and many patients may have several factors that contribute. These disorders can be broadly categorized into those that involve nocturnal sleep and daytime manifestations such as excessive daytime sleepiness. Some sleep disorders, in particular REM sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS) may arise as a primary manifestation of PD, reflecting the anatomic areas affected by the neurodegenerative process. Appropriate diagnosis of the sleep disturbance affecting a PD patient can lead to specific treatments that can consolidate nocturnal sleep and enhance daytime alertness.

Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease

To explore the clinical significance of restless legs syndrome (RLS) in Parkinson's disease (PD) and the causal relationship between these two disorders, we made a comparison of both the prevalence of RLS and the severity of sleep disturbance manifested on the Pittsburg Sleep Quality Index (PSQI) between patients with PD (n=165) and age- and sex-matched control subjects (n=131). The prevalence of RLS diagnosed by clinical interview was significantly higher in PD patients than in control subjects (12% vs. 2.3%). PSQI score was significantly higher in PD patients with RLS than in both patients without RLS and controls. However, PSQI score was not statistically different between the latter two groups. Among the PD patients with RLS, only 2 had a positive family history of RLS. Only 3 PD patients had requested treatment for the disorder. Our results emphasize the etiological link between RLS and PD in a Japanese cohort, and the existence of RLS is thought to be one of the most important factors aggravating sleep disturbance in PD, despite the low RLS severity.

Provisional diagnostic criteria for depression in Parkinson's disease: Report of an NINDS/NIMH Work Group

Mood disorders are the most common psychiatric problem associated with Parkinson's disease (PD), and have a negative impact on disability and quality of life. Accurate diagnosis of depressive disturbances in PD is critical and will facilitate the testing and use of new interventions; however, there are no clear diagnostic criteria for depressive disorders in PD. In their current form, strict Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are difficult to use in PD and require attribution of specific symptoms to PD itself or the depressive syndrome. Additionally, DSM criteria for major depression and dysthymia exclude perhaps half of PD patients with comorbid clinically significant depression. This review summarizes an NIH-sponsored workshop and describes recommended changes to DSM diagnostic criteria for depression for use in PD. Participants also recommended: (1) an inclusive approach to symptom assessment to enhance reliability of ratings in PD and avoid the need to attribute symptoms to a particular cause; (2) the inclusion of subsyndromal depression in clinical research studies of depression of PD; (3) the specification of timing of assessments for PD patients with motor fluctuations; and (4) the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and intended to be defined further and validated but provide a common starting point for clinical research in PD-associated depression.

Neuropharmacological Treatment of Mental Dysfunction in Parkinson’s Disease

Many patients with Parkinson's Disease (PD) experience significant cognitive and mood impairment -even early in the course of the disease. These mental impairments are only partially responsive to levodopa treatment and are often as disabling as the motor impairment, particularly in mid and late stages of the disease. Investigators have recently begun a search for new agents that can effectively treat mental dysfunction of PD. Although there have been only a handful of properly controlled clinical trials of interventions targeted at amelioration of mental dysfunction in PD, progress has been made. Based on the available evidence, targeting catecholaminergic and cholinergic function may be an effective strategy for amelioration of cognitve, mood and psychiatric disturbances in PD.

Dopaminergic influence on disturbed spatial discrimination in Parkinson's disease

Various sensory symptoms and disturbed sensory perception are often observed in patients with idiopathic Parkinson's disease (PD). The basis of sensory disturbance in PD is unknown but possibly reflects a role for the basal ganglia in sensory processing. To investigate the relationship between the sensory dysfunction and dopaminergic deficiency in PD, we measured spatial discrimination using the Grating Orientation Task in 21 drug-naive patients with PD, before and after long-term antiparkinson therapy, and 25 age-matched healthy controls. The grating orientation threshold was significantly higher in patients (3.03 +/- 0.84) than controls (2.03 +/- 0.79). After 3 to 10 months of antiparkinson therapy, the grating orientation threshold was significantly lowered (2.66 +/- 0.84), although it was still higher than that in controls. Improvement in the patients' sensory function was significantly correlated with motor improvement (r = 0.44). These results suggest that sensory dysfunction in Parkinson's disease is related at least in part to the dopaminergic deficit.

Psychiatric comorbidities in patients with Parkinson disease and psychosis.

To determine the prevalence and impact of comorbid psychiatric disturbances in Parkinson disease (PD) patients with psychosis. Subject data were derived from a research database of 116 PD patients participating in standardized motor, cognitive, psychiatric, and caregiver assessments. There were 25 patients (22%) with psychosis manifest as hallucinations (n = 9), delusions (n = 1), or hallucinations and delusions (n = 15) and 25 patients (22%) who had no current or past psychiatric comorbidities (PDN). In the psychotic group, 44% had psychosis only (PSY), and 56% had psychosis plus at least one other comorbid psychiatric disturbance (PSY+), including depressive disorders (71%), anxiety disorders (21%), apathetic syndromes (14%), and delirium (14%). There were no differences in age, sex, education, or age onset or duration of PD among the PSY, PSY+, and PDN groups. Both psychotic groups had greater motor, functional, and frontal cognitive deficits and increased caregiver burden scores relative to PDN. PSY+ showed greater global and selective cognitive deficits compared to PDN. Psychosis was a primary predictor of caregiver burden, whereas depressive symptoms indirectly enhanced motor impairments. Nonpsychotic psychiatric disturbances, especially affective disturbances, are common comorbidities in PD patients with psychosis and warrant clinical attention to reduce morbidity and caregiver distress.

Snoring and excessive daytime sleepiness in Parkinson's disease

Recent recognition of daytime sleepiness in Parkinson's disease (PD) has prompted a search for its causes. Sleepy patients may be more susceptible to sleep attacks after the use of dopamine agonists and the recognition of sleep disturbances in PD may influence important therapeutic decisions. To identify clinical factors influencing excessive daytime sleepiness (EDS) and sleep complaints in PD, we studied 86 consecutive patients with clinical diagnosis of PD using a sleep questionnaire, the Epworth Sleepiness Scale, the Unified Parkinson's Disease Rating Scale and the Montgomery and Asberg Depression Rating Scale. Patients with cognitive dysfunction were not included in the study. We found that 49 patients (53.3%) had insomnia, 45 (49.9%) restless legs syndrome (RLS), 51 (55.4%) vivid dreams, 61 (71.8%) snoring and 29 (31.5%) had EDS. RLS was more frequent in patients with longer duration of illness. Snoring was the most important risk factor associated with EDS (OR=3.64, 95% CI=1.11–11.9, P=0.03) and a marginal association between motor dysfunction and EDS was observed (OR=1.06, 95% CI=1.00–1.12, P=0.05).

Gait dynamics in Parkinson's disease: relationship to Parkinsonian features, falls and response to levodopa

Objectives: Patients with Parkinson's disease (PD) have an increased risk of falling that has yet to be fully explained. To better understand the gait disturbance in PD and the factors that contribute to falls, we quantitatively evaluated: (1) the relationship between gait variability (a marker of fall risk in other populations), fall history, and other parkinsonian features, and (2) the effects of levodopa on these relationships. Methods: The average stride time and stride-to-stride variability were measured using force-sensitive insoles during comfortable walking. Fall frequency, motor control, function, and mental health were measured using the Unified Parkinson's Disease Rating Scale (UPDRS), the Mini-Mental State Exam (MMSE), and the timed motor tests of the Core Assessment Program for Intracerebral Transplantations (CAPIT) in 32 subjects with idiopathic PD, in an “off” (unmedicated) state and again in an “on” (medicated) state. Results: Average stride time was not associated with any UPDRS or CAPIT measure and was similar in fallers and non-fallers in “off” and “on” states (p>0.27). Stride time variability was significantly associated with fall frequency as well as with total scores on the CAPIT and the UPDRS, ADL abilities, and motor function. Stride time variability and falls were not related to tremor, rigidity or bradykinesia in the “off” state. 41% of subjects reported one or more falls. Stride time variability was 8.8±7.9% in fallers and 4.2±1.3% in non-fallers (p<0.009). Stride time variability significantly improved in response to levodopa, both in fallers and non-fallers, but remained increased in fallers (vs. non-fallers). Conclusions: The patho-physiology responsible for impaired stride-to-stride regulation of gait timing is apparently independent of other cardinal features of PD, i.e., tremor, rigidity, or bradykinesia, but is responsive to levodopa. Stride-to-stride variability is especially impaired among PD subjects with a history of falls, suggesting, for the first time, the possibility of exaggerated impairment of internal clock function in PD fallers.

Approaching disturbed sleep in late Parkinson's Disease: first step toward a proposal for a revised UPDRS

A patient in stage 3–4 of the Unified Parkinson's Disease Rating Scale (UPDRS), or in stage 4–5 of Hoehn and Yahr staging scale, or a patient with 0–50% activities of daily living scale of Schwab and England is considered a Late Parkinson's Disease (LPD) patient. The prevalence of disturbed sleep in Parkinson's Disease (PD) was found to vary according to an objective rating, from 60 to 98%. The factors predicting the quality of life in PD patients are: depression, sleep disturbances and dependence. The present article proposes the insertion of the following items as a chapter in a revised UPDRS based on updated knowledge in sleep arousal disturbances in PD. V. SLEEP-AROUSAL DISTURBANCES: Sleep disturbances 43. Light fragmented sleep (LFS) 44. Sleep-related breathing disorders (SRBD) 45. Restless legs-periodic leg movements during sleep (RLS-PLM) 46. REM behavior disorders (RBD) 47. Sleep-related hallucinations (SRH) 48. Sleep-related psychotic behavior (SRPB) Arousal disturbances 49. Sleep attacks (SA) 50. Excessive daytime sleepiness (EDS) Approaching the treatment of disturbed sleep in LPD means postponement of the institutionalization of the LPD patient, allowing the spouse or the caregiver a quiet nights sleep. This approach consists of three steps, each one of major importance. (1) Correct diagnosis based on detailed anamnesis of the patient, of the spouse or of the caregiver; a one week recording on a symptom diary (log) by the patient or the caregiver; excluding co morbidities. Then choosing the most appropriate sleep test, if necessary: polysomnography (PSG), multiple sleep latency test (MSLT), multiple wake latency test (MWLT), actigraphy or video-PSG. This first step allows the diagnosis of one of the above mentioned sleep-arousal disturbances. (2) The non-specific therapeutic approach consists of: (a) checking the sleep effect on motor performance: beneficial, worse or neutral. (b) Dopaminergic adjustment is necessary due to the progression of the nigrostriatal degeneration and the increased sensitivity of the terminals which alter the normal modulator mechanisms of motor centers in LPD patients. Among the many neurotransmitters of the nigro-striatal pathway one can distinguish two with a major influence on REM and non-REM sleep. REM sleep corresponds to an increased cholinergic receptor activity and a decreased dopaminergic activity. This is the reason why REM sleep deprivation by suppressing cholinergic receptor activity ameliorates LPD motor symptoms. l-Dopa and its agonists by suppressing cholinergic receptors suppress REM sleep. l-Dopa has also an arousal effect on Non-REM sleep, repeatedly awakening the patient and enhancing the fragmentation due to the involuntary movements. (c) Socio–physical assistance. (3) The specific therapy consists of: LFS-Sinemet CR, Tolcapone, Intranasal Desmopressin, Domperidon, Cisapride and neurosurgery; SRBD-CPAP, UPPP, nasal interventions, losing weight; RLS-PLM-Benzodiazepine (Clonazepam), Opioid, Apomorphine infusion; RBD-Clonazepam and dopaminergic agonists; SRH-Clozapine, Risperidone; SRPD-Nortriptyline, Clozapine, Olanzepine; SA-adjustment; EDS-arousing drugs. Each therapeutic approach must be tailored to the individual LPD patient.

Abnormalities in the stride length-cadence relation in parkinsonian gait.

The purpose of this investigation was to clarify abnormalities in the stride length-cadence relation in gait hypokinesia in Parkinson's disease (PD). A second aim was to investigate the effect of levodopa medication on the foot-step pattern. In the first experiment, 20 subjects with idiopathic PD and 20 age-, sex-, and height-matched controls performed a series of 10 m walking trials at cadence rates ranging from 40 steps/min to 180 steps/min. Cadence rates were set by an electronic metronome, and gait patterns were measured by using a footswitch stride-analyzer system. By instructing subjects to concentrate on walking in time to the metronome beat, the baseline stride length could be monitored for a range of velocities with the compensatory effects of cadence removed. Linear-regression analysis revealed that the mean slope for the regression of stride length against cadence was not different from normal in PD, although there was a statistically significant difference in mean intercept between the PD group (0.25) and the control group (0.59); [t (19) = -4.76; p = 0.0001]. The second experiment evaluated the effects of levodopa on stride-length regulation in 10 subjects with idiopathic PD on average 45 min before and after the first morning dose was administered. There was a statistically significant increase in stride length for all cadence rates from premedication to postmedication phases and the maximal stride length was achieved at higher cadence rates after medication. The slope of the regression of stride length against cadence did not alter according to medication status, although the mean intercept was significantly lower before levodopa (-0.06) compared with after levodopa (0.27); [t (9) = -3.83; p = 0.004]. These results suggest that defective scaling of stride length underlies gait disturbance in PD.

Decreased number of oxytocin-immunoreactive neurons in the paraventricular nucleus of the hypothalamus in Parkinson's disease.

We determined the number of immunocytochemically identified oxytocin (OXT) and vasopressin (AVP) neurons in the paraventricular nucleus (PVN) of the human hypothalamus of six Parkinson's disease (PD) patients ranging from 59 to 83 years of age. Six subjects without a primary neurologic or psychiatric disease, ranging from 69 to 88 years of age, served as controls. The OXT-immunoreactive cell number in the PVN of the PD patients was 22% lower than that of the control subjects. Although Lewy bodies were present in the nucleus basalis of Meynert, there were no Lewy bodies in the PVN of these patients. Doubt is raised about the presumed direct relationship between the presence of Lewy bodies and neuronal degeneration in PD. The AVP-immunoreactive cell number in the PD patients showed a similar decreasing trend, but the 18% reduction failed to reach statistical significance. The presence of tyrosine hydroxylase-positive neurons in the PVN was not affected in PD patients, supporting the notion that dopaminergic neurons of the mesencephalon, but not of the hypothalamus, are affected in PD. The decreased number of OXT-containing neurons in the PVN suggests that dopamine may be important for the function of these neurons and may provide a neural basis for some autonomic and endocrine disturbances in PD.