Combined beneficial effect of rasagiline on motor function and depression in de novo PD.

OBJECTIVES: To investigate prokinetic and antidepressive effects of rasagiline in de novo Parkinson disease (PD). MATERIALS AND METHODS: Patients with newly diagnosed PD with comorbid untreated depression were randomly assigned to rasagiline monotherapy 1 or 2 mg/d. Unified Parkinson's Disease Rating Scale Part 2 (Activity of Daily Living) and Part 3 (Motor Function), and Hamilton Depression Rating Scale (HDRS) assessments were carried out by a blinded investigator in each patient at baseline and after 8 weeks of rasagiline treatment. RESULTS: Both groups showed equal motor improvement at the end point. The improvements of HDRS score and activity of daily living were significantly more pronounced with rasagiline, 2 mg/d, than rasagiline, 1 mg/d (P = 0.0002). The treatment with rasagiline, 2 mg/d, improved symptoms in all HDRS core depression symptoms and specifically those not considered to be influenced by motor function: mood, guilt, psychic anxiety, and hypochondria. CONCLUSION: Our results suggest that antidepressive effect seen in higher dosage of rasagiline may be not related to the motor improvement.

Health-related quality of life and its determinants in the urban Russian population with major depressive disorder: a cross-sectional study.

OBJECTIVE: Depressive disorders pose a major challenge to healthcare in the countries of the former Soviet Union. The objective of the current study was to evaluate health-related quality of life (HrQoL) and its determinants in outpatients with major depressive disorder in an urban Russian population. METHODS: We consecutively recruited 100 urban Russian outpatients with major depression and 100 non-depressed controls who were matched for age and sex. The severity of their depression was assessed using the Hamilton Depression Rating Scale (HDRS). HrQoL was evaluated using the EuroQol (the EQ-5D and the visual analogue scale, EQ VAS). Independent determinants of HrQoL were identified using multiple regression analysis. RESULTS: The mean EQ VAS score was 43.0 +/- 27.4 in patients with depression compared to 81.4 +/- 14.7 in the controls (p < 0.01). Out of the domains of the EQ-5D, "anxiety/depression," "usual activities," and "self-care" were the most impaired. Independent determinants of reduced HrQoL were: severity of depression according to the HDRS; violent suicide attempts; suicide attempts in the past; and drug addiction. CONCLUSIONS: HrQoL is considerably reduced in Russians with major depression. The disease-specific patterns of HrQoL impairment and the independent determinants of HrQoL identified in our study could be addressed in focused healthcare programs and clinical trials. Comorbid drug addiction as a determinant of HrQoL should receive greater attention in the management of depressive disorders in urban Russian populations.

Depression in elderly patients with Alzheimer dementia or vascular dementia and its influence on their quality of life.

BACKGROUND: Alzheimer dementia (AD) and vascular dementia (VD) are the most common causes of dementia in the elderly. Depression is an important co-morbid disorder in these diseases, which is often challenging to recognize. We investigated the prevalence of depression in patients with AD and VD and estimated the influence of depression on the health-related quality of life (HrQoL) in these patients. MATERIALS AND METHODS: We evaluated prevalence of depression in consecutively recruited patients with AD or VD (n= 98). Depression was diagnosed according to criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and scored using the Geriatric Depression Scale. The EuroQol (EQ-5D and visual analogue scale) was applied to evaluate HrQoL. The severity of cognitive impairment was measured by the Mini-Mental State Examination (MMSE). Multiple regression analysis was used to identify factors predicting severity of depression. RESULTS: The prevalence of depression in AD/VD was 87%. In comparison to the general population, HrQoL measured on the visual analogue scale was reduced by 54% in patients with AD/VD. In the dimension "anxiety/depression" of the EQ-5D, 81% of patients with AD/VD had moderate or severe problems. Depression showed significant association with reduced HrQoL (P<0.01). Independent predictors of more severe depression were older age, male gender, better MMSE scores and being not married. CONCLUSIONS: Depression is a prevalent psychiatric co-morbidity in patients with AD/VD, which is often under-diagnosed being masked by cognitive impairment. Depression is a predictor of reduced HrQoL in elder people with AD/VD. Therefore, they should be screened for presence of depressive symptoms and receive adequate antidepressant treatment.

Neuromodulatory neurotransmitters influence LTP-like plasticity in human cortex: a pharmaco-TMS study.

Long-term potentiation (LTP) of synaptic efficacy is considered a fundamental mechanism of learning and memory. At the cellular level a large body of evidence demonstrated that the major neuromodulatory neurotransmitters dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) influence LTP magnitude. Noninvasive brain stimulation protocols provide the opportunity to study LTP-like plasticity at the systems level of human cortex. Here we applied paired associative stimulation (PAS) to induce LTP-like plasticity in the primary motor cortex of eight healthy subjects. In a double-blind, randomized, placebo-controlled, crossover design, the acute effects of a single oral dose of the neuromodulatory drugs cabergoline (DA agonist), haloperidol (DA antagonist), methylphenidate (indirect NE agonist), prazosine (NE antagonist), tacrine (ACh agonist), and biperiden (ACh antagonist) on PAS-induced LTP-like plasticity were examined. The antagonists haloperidol, prazosine, and biperiden depressed significantly the PAS-induced LTP-like plasticity observed under placebo, whereas the agonists cabergoline, methylphenidate, and tacrine had no effect. Findings demonstrate that antagonists in major neuromodulatory neurotransmitter systems suppress LTP-like plasticity at the systems level of human cortex, in accord with evidence of their modulating action of LTP at the cellular level. This provides further supportive evidence for the known detrimental effects of these drugs on LTP-dependent mechanisms such as learning and memory.

Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation.

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders.

Initial experience with ropinirole PR (prolonged release).

Ropinirole is a non-ergolinic dopamine agonist, which has been used for over 10 years for the treatment of Parkinson's disease. A new formulation (PR = prolonged release) has been developed, which allows the drug to be released slowly (continuously) so that it only has to be given once daily. Switching from the previous ropinirole immediate release ( ropinirole IR) to the prolonged release (ropinirole PR) formulation at the nearest equivalent total daily dose, can take place overnight and the acceptance and tolerability are good. The advantages are once-daily dosing, faster titration with good tolerability and more stable plasma levels. The new formulation is regarded as valuable addition to the currently available medications.

Employment, medical absenteeism, and disability perception in Parkinson's disease: A pilot double-blind, randomized, placebo-controlled study of entacapone adjunctive therapy.

The objective of this study was to test the impact of entacapone (ENT) addition to levodopa with a decarboxylase inhibitor (LD) in full-time-employed patients with Parkinson's disease (PD), focusing on retirement rates, medical absenteeism, self-perception of disability, as well as motor assessments of parkinsonism, motor fluctuations, and dyskinesias. Thirty full-time-employed PD patients (disease onset before age 60 years) and on optimized monotherapy with LD exhibiting minor motor fluctuations or dyskinesias were entered into a 2-year randomized double-blind placebo-controlled study of ENT adjunctive therapy. The outcome measures were the number of full-time-employed patients at study end, cumulative days of medical absenteeism, patient-completed disability assessments, diary records, and the Unified Parkinson's Disease Rating Scale-based measures of motor fluctuations and dyskinesias. LD + ENT treatment was associated with a lower retirement rate (2 [17%] of 12 vs. 6 [50%] of 12; P = 0.12), lower absenteeism rate (21.5 vs. 43.5 days; P < 0.0001), improved self-perception of disability progression over 2 years (change score 1.0 vs. 4.5; P < 0.0001), and lower scores for both motor fluctuations and dyskinesia assessments compared to LD monotherapy. In this pilot study, LD with ENT adjunctive therapy positively influenced employment rate over 2 years; this effect was associated with reduced motor complications and patient perceptions of stabilized disability.

Pharmacological modulation of plasticity in the human motor cortex.

Ischemic cerebral stroke is the leading cause of long-term disability among adults in industrialized countries. One fundamental but still not sufficiently solved question is how to improve disability after stroke. Here, evidence will be reviewed on how pharmacological treatment modulates plasticity and learning in the intact human motor cortex. It will be argued that these data may be useful for advancing the concepts of pharmacotherapy for recovery after stroke.

Determinants of autonomic dysfunction in idiopathic Parkinson's disease.

OBJECTIVES: To determine demographic or disease-related factors that may influence the severity of autonomic dysfunction in idiopathic Parkinson's disease (IPD). METHODS: 532 patients with IPD aged between 55 and 75 years were included. Severity of autonomic dysfunction was assessed using a 9-item autonomic dysfunction score (ADS). In addition, several demographic factors (e. g. age, gender, comorbidities) and disease- related (e. g. motor stage, disease duration, antiparkinsonian therapy) factors were recorded. A group of 67 age-matched healthy volunteers served as a control group. Demographic and clinical data of this cross-sectional survey were analyzed by a logistic stepwise regression model to determine independent predictors of autonomic dysfunction. RESULTS: IPD patients showed significantly higher ADS values than controls, even in the youngest age groups and in mild disease stages. Hoehn & Yahr (H&Y) stage, disease duration, age at onset and various therapy combinations all showed significant correlations with ADS. However, stepwise logistic regression revealed that age (OR 10.71; CI 7.17-16.0) and arterial hypertension (OR 3.05; CI 1.66-5.58) were the only independent risk factors associated with autonomic dysfunction. Linear regression indicated that ADS increases with age in controls as well as in patients, but with a significantly steeper slope in the latter. CONCLUSIONS: Autonomic dysfunction as an inherent feature of IPD is present already in early disease stages. According to a logistic regression model, the severity of autonomic dysfunction in IPD is primarily related to demographic but not to disease-related factors. This and the differences in predictors for motor versus autonomic decline may indicate at least partly independent neurodegenerative processes.

Modification of motor cortical excitability by an acetylcholinesterase inhibitor.

Acetylcholine powerfully modulates the excitability of neocortical neurones and networks. This study applied focal transcranial magnetic stimulation (TMS) to eight healthy subjects to test the effects of a single oral dose of 40 mg tacrine, an acetylcholinesterase inhibitor, on motor cortical excitability. It was found that tacrine decreased short-interval intracortical inhibition, and increased intracortical facilitation and short-interval intracortical facilitation. Motor thresholds, motor evoked potential amplitude, cortical silent period (CSP) duration, and measures of spinal and neuromuscular excitability remained unchanged. The effects peaked at 2-6 h and fully reversed after 24 h. All effects can be explained by a reduction of motor cortical GABAergic inhibitory neurotransmission via activation of presynaptic muscarinic M2 receptors, but other more complex mechanisms may also have contributed and are discussed. The findings predict that acetylcholine has the potential to promote plasticity and learning in human motor cortex.

Parenteral ziprasidone: a new atypical neuroleptic for emergency treatment of psychosis in Parkinson's disease?

This is a report on a case series of five patients with psychosis in Parkinson's disease who were treated successfully with an intramuscular injection of ziprasidone (10-20 mg) for acute agitation. No deterioration of motor function or other clinically relevant side effects were seen.

Differences in age at onset and familial aggregation between clinical types of idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) can be subdivided by its patterns of motor symptoms into tremor-dominant (TDT), akinetic-rigid (ART), and mixed type (MT). Our objective was to determine whether age at onset and family history are different in these three types. In total, 366 patients with PD were assigned in a standardized approach to one of the three subtypes. Age at onset and family history were obtained in all patients and all presumably affected family members were examined. Mean ages at disease onset were similar in all three groups, but distribution of age at onset was markedly different: monophasic in TDT with a peak around 60 years, biphasic in ART with two peaks, one in the middle of the sixth decade (earlier onset, ART-EO), another during the first half of the seventh decade (later onset, ART-LO), and increasing with age only in MT patients A positive family history was significantly associated only with TDT (odds ratio = 5.7) and ART-EO (odds ratio = 7.8), but not with MT or ART-LO patients. Segregation analysis suggested an autosomal recessive mode of transmission in ART-EO and an autosomal dominant mode of transmission in TDT.

The alpha2-adrenergic agonist guanfacine reduces excitability of human motor cortex through disfacilitation and increase of inhibition.

OBJECTIVE: To test the acute effects of the alpha2-adrenoceptor agonist guanfacine (GFC) on motor excitability in intact humans. METHODS: Eight healthy right-handed adults received a single oral dose of 2 mg of GFC. Motor cortex excitability was tested by focal transcranial magnetic stimulation of the hand area of the left motor cortex. Motor evoked potentials (MEP) were recorded from the right abductor pollicis brevis muscle. In addition, spinal and neuromuscular excitability were tested. All measures were obtained immediately before GFC intake (baseline), and 2, 6, and 24 h later. RESULTS: GFC decreased the slope of the MEP intensity curve, increased paired-pulse short-interval intracortical inhibition, and decreased paired-pulse intracortical facilitation and I-wave facilitation. These effects were maximal at 2-6 h and returned to baseline at 24 h. Motor threshold, cortical silent period, and the measures of spinal (peripheral silent period, F waves) and neuromuscular excitability (maximum M wave) remained unaffected. CONCLUSIONS: This is the first study on the effects of an anti-noradrenergic drug on human motor cortex excitability. GFC reduced cortical excitability by disfacilitation and increased inhibition. These findings support the idea that anti-noradrenergic drugs are detrimental for cortical plasticity and learning which are down-regulated by disfacilitation or increased inhibition.

Methylphenidate facilitates and disinhibits the motor cortex in intact humans.

Animal experiments show that motor recovery after focal brain injury is accelerated by the indirect norepinephrine agonist methylphenidate (MPH). The underlying mechanisms are unknown, but an MPH-induced increase in cortical excitability has been advocated. Here, we tested the acute effects of a single oral dose of 40 mg MPH (Ritalin) on motor cortical excitability in eight healthy subjects using focal transcranial magnetic stimulation. MPH increased the slope of the motor evoked potentials (MEP) intensity curve in a hand muscle, reduced short-interval intracortical inhibition, and increased I-wave facilitation. MEP threshold, cortical silent period and measures of spinal and neuromuscular excitability remained unaffected. Findings support the idea that MPH promotes accelerated motor recovery after lesion through facilitation and disinhibition.

Complex modulation of human motor cortex excitability by the specific serotonin re-uptake inhibitor sertraline.

Monoamines are powerful modulators of cortical function. Serotonin has complex excitatory and inhibitory effects on animal cortex. Here, the effects of a single oral dose (100mg) of the selective serotonin re-uptake inhibitor sertraline on human motor cortex excitability were investigated in healthy subjects. Transcranial magnetic stimulation was used to test motor threshold, motor evoked potential intensity curve, cortical silent period, paired-pulse inhibition and facilitation and I-wave facilitation. Sertraline resulted in a steeper intensity curve and in depressed paired-pulse facilitation (PPF). All other measures and spinal and neuromuscular excitability remained unaffected. The steeper intensity curve points to an increased excitability of the cortico-spinal neurone, while the depressed PPF suggests an enhanced control of the cortico-spinal neurone by inhibitory interneurones. These features may improve the signal-to-noise ratio of output cells in human motor cortex.