A new bedside test of gestures in stroke: the apraxia screen of TULIA (AST).

BACKGROUND: Apraxia in patients with stroke may be overlooked, as clumsiness and deficient gestural communication are often attributed to frequently coexisting sensorimotor deficits and aphasia. Early and reliable detection of apraxia by a bedside test is relevant for functional outcome in patients with stroke. The present study was aimed at constructing a new bedside screening test for apraxia, called the Apraxia Screen of TULIA (AST), based on the comprehensive standardised Test for Upper-Limb Apraxia (TULIA). METHODS: First, an item-reduction analysis of the TULIA (48 gestures) was performed, based on the methods of classical test theory and on a larger sample of patients with stroke (n=133) and matched healthy controls (n=50). Stepwise elimination of items resulted in a set of 12 items, demonstrating high internal consistency (Cronbach alpha=0.92). The six-point scoring method of the TULIA was dichotomised to the score levels pass and fail. In the second part of this study the validity of the AST was assessed prospectively in a new cohort of patients with stroke (n=31) by using the Pearson correlation analysis and binary classification display with the TULIA. RESULTS AND DISCUSSION: Validation of the 12-item AST with the TULIA showed a remarkable diagnostic reliability with high specificity, sensitivity and positive predictive value, for the presence and severity of apraxia. The AST is shown to be a reliable and valid bedside test in patients with stroke, allowing a straightforward assessment of apraxia within a few minutes.

Impaired finger dexterity in Parkinson's disease is associated with praxis function.

A controversial concept suggests that impaired finger dexterity in Parkinson's disease may be related to limb kinetic apraxia that is not explained by elemental motor deficits such as bradykinesia. To explore the nature of dexterous difficulties, the aim of the present study was to assess the relationship of finger dexterity with ideomotor praxis function and parkinsonian symptoms. Twenty-five patients with Parkinson's disease participated in the study. Their left and right arms were tested independently. Testing was done in an OFF and ON state as defined by a modified version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Finger dexterity was assessed by a coin rotation (CR) task and ideomotor praxis using a novel test of upper limb apraxia (TULIA), in which the patients were requested to imitate and pantomime 48 meaningless, as well as communicative and tool-related gestures. Coin rotation significantly correlated with TULIA irrespective of the motor state and arm involved, but not with the MDS-UPDRS. This association was significantly influenced by Hoehn and Yahr stage. The strong association of finger dexterity with praxis function but not the parkinsonian symptoms indicates that impaired finger dexterity in Parkinson's disease may be indeed apraxic in nature, yet, predominantly in advanced stages of the disease when cortical pathology is expected to develop. The findings are discussed within a cognitive-motor model of praxis function.

[Rehabilitation of parkinsonian patients]. / Rehabilitation von Parkinsonpatienten.

Although most parkinsonian patients greatly benefit from medical and/or surgical treatment, their clinical management should not be limited to these two interventions. Axial symptoms, freezing, postural instability, speech and swallowing problems may be drug-resistant, and disability may persist in spite of improvement of motor symptoms. A coordinate interdisciplinary approach facilitates the clinical management of the disease. Physiotherapy, occupational therapy and speech therapy may contribute to reduce impairment and improve quality of life; a psychological and social support of patients and caregivers helps them carrying the burden of the disease; counseling through a specialized nurse may give practical solutions to problems like bladder incontinence, symptomatic hypotension or hypersalivation. As sensory cueing may help patients bypassing the disease-specific motor control deficits, it should be included in training programs. Rehabilitatory interventions are part of the standards of care of Parkinson's disease and their efficacy is supported by several neurophysiological and clinical investigations. However, the poor methodological quality of most clinical studies as compared with the standard of pharmacological investigations fails to provide clear-cut evidence in favour of rehabilitation.

Growth hormone secretion in Alzheimer's disease: 24-hour profile of basal levels and response to stimulation and suppression studies.

The 24-h growth hormone secretory pattern and GH response to growth hormone releasing hormone, the alpha 2-adrenoceptor agonist clonidine and the somatostatin-analogue SMS 201-995 were evaluated in 9 patients with Alzheimer's disease and 9 age- and body body-matched control subjects. The secretory profile did not differentiate between patients and controls. Both secreted the largest amount of GH during the early nighthours between 22.00-02.00, whereas the majority of daytime GH levels were below the assay's detection limit (0.4 ng/ml). No difference was found in GH response to GHRH between patients and controls. All subjects showed significantly enhanced GH secretion after GHRH. Dividing the patients into two groups according to age-of-onset (less than 60 years greater than), there was a trend toward larger GH responses to GHRH for the early-onset group. No other parameter differentiated the groups. GH levels after clonidine were blunted in all subjects but one AD patient, probably due to an age-dependent attenuation frequently observed in subjects over 45 years of age. Finally, the administration of the somatostatin-analogue did not render conclusive results, since spontaneous decline of GH concentration was already beginning 2 hours before the drug was given and continued steadily throughout the observation period. In conclusion, patients with only mild to moderate degree of Alzheimer's disease have no prominent changes in GH regulation.

Acute effects of pulsatile levodopa administration on central dopamine pharmacodynamics.

Inconsistencies in the response to individual levodopa doses occur in most patients with advanced Parkinson's disease (PD). To investigate the possible development of acute tachyphylaxis, we evaluated the effects of repeated injections of intravenous levodopa in 10 PD patients with motor fluctuations by administering, during a single day, a previously determined optimal levodopa dose repeatedly each time motor function returned to baseline. Peak antiparkinsonian response was lower by 20%, and peak plasma levodopa levels lower by 35% following the first dose compared with all subsequent doses. Neither peak dyskinesia scores nor the duration of motor response changed significantly with successive levodopa doses. These data suggest that pulsatile levodopa administration does not acutely alter dopamine receptor responsiveness, and that other pharmacokinetic and pharmacodynamic factors contribute to the dose-to-dose variability in response to levodopa.

Partial dopamine agonist therapy of levodopa-induced dyskinesias.

We administered the partial dopamine agonist terguride under controlled conditions to patients with Parkinson's disease (PD), both as monotherapy and in conjunction with intravenous levodopa. Terguride produced a dose-dependent decrease in levodopa-induced dyskinesias (up to 53%) in seven patients without concomitant worsening of parkinsonism, and had no significant antiparkinsonian effect when administered alone. Partial dopamine agonists may hold some promise in the adjuvant therapy of patients with advanced PD.

Rationale for continuous dopaminomimetic therapy of Parkinson's disease.

Levodopa combined with carbidopa (Sinemet) remains the most effective approach to the symptomatic relief of Parkinson's disease. Over time, however, an increasing number of parkinsonian patients evidence motor response complications, notably abnormal involuntary movements and motor fluctuations. Clinical pharmacologic studies suggest that these phenomena may arise as a consequence of factors reflecting both natural disease progression and levodopa toxicity. Simple wearing-off responses appear primarily related to advancing degenerative changes afflicting the dopamine system. The appearance of peak-dose dyskinesias and complex, random motor fluctuations of the on-off type, on the other hand, may signal secondary postjunctional changes arising as a consequence of chronic intermittent excitation of postsynaptic dopamine receptors that are normally tonically stimulated. Therapeutically, prompt correction of wearing-off fluctuations can ordinarily be achieved by measures that deliver dopaminomimetics continuously to the central nervous system. In contrast, fluctuations of the on-off type initially persist despite stable circulating levodopa levels. With continuous levodopa treatment, however, the threshold for dyskinesias begins to rise and the dose-response relation shifts to the right; clinically, the severity of both dyskinesias and on-off fluctuations tends to diminish. It is thus tempting to speculate that the early and continuing treatment of Parkinson's disease with compounds providing a relatively constant level of central dopamine stimulation will preclude wearing-off phenomena and mitigate on-off fluctuations and severe dyskinesias.

Deprenyl effects on levodopa pharmacodynamics, mood, and free radical scavenging.

Clinical evidence suggests that deprenyl may slow progression of Parkinson's disease, although mechanisms underlying this putative neuroprotective action remain poorly understood. To address this issue, we studied deprenyl in 12 parkinsonian patients using a single-blind, placebo-controlled, crossover design. After 1 month, deprenyl (10 mg/d) decreased the optimal levodopa requirement by 24% (oral) and 16% (intravenous). Levodopa-induced dyskinesias were prolonged by 430%, and antiparkinsonian action by 44%. Mood improved by 47%. One month after withdrawing deprenyl, effects on dyskinesias and mood had yet to return to baseline. There was no change in activities of circulating glutathione peroxidase, glutathione reductase, glutathione transferase, superoxide dismutase, and catalase, nor in levels of lipid peroxide and vitamin E. Deprenyl also failed to modify CSF levels of total glutathione and activities of glutathione peroxidase or superoxide dismutase. These effects on levodopa pharmacodynamics and mood complicate the interpretation of available investigations of deprenyl's neuroprotective action and increase the risk of adverse effects of levodopa.

Opioid peptides in Parkinson's disease: effects of dopamine repletion.

Neurotransmitters other than dopamine, including neuropeptides, could have important pathophysiologic and therapeutic roles in Parkinson's disease. Both Met-enkephalin, the main transmitter of the striatopallidal pathway, and dynorphin, one of the co-transmitters of the striatonigral pathway display complex anatomic and biochemical interactions with the basal ganglionic dopamine system. In this study, the cerebrospinal fluid content of a proenkephalin derivative, Met5 enkephalin-Arg6-Gly7-Leu8 (MERGL), was found in significantly low concentrations in parkinsonian patients following overnight withdrawal of all medications compared with control subjects, and failed to change after at least 16 h of steady-state, optimal doses of levodopa infusion intravenously. MERGL levels increased with advancing age among normal individuals but not among patients with Parkinson's disease. In contrast dynorphin A(1-8) levels were not different between the two study groups, did not change with levodopa therapy, and failed to correlate with age or any indices of disease progression. These observations, consistent with post-mortem studies on Parkinson brains and contrary to findings in animal models of Parkinsonism, suggest that abnormality of the enkephalin system in this disease is due to involvement of these striatal neurons in the primary pathologic process.

The role of MAO-b inhibitors in the treatment of Parkinson's disease.

The classical treatment of Parkinson's disease (PD) using L-dopa plus a peripheral decarboxylase inhibitor (DI) often leads after 3-5 years to the onset of the so-called long-term L-dopa syndrome (LTS). LTS could depend on the chronic overload of L-dopa + ID and could be due to a consequent "receptor disease" and derangement of the neuronal functionality mainly in regard to the enzymatic chains, storage mechanisms and hyperactivity of the monoamine oxidase type B (MAO B). Deprenyl is a selective MAO-B inhibitor thought to be able to slow down the catabolism of dopamine and therefore to allow a decrease of the therapeutic regimen of L-dopa while in the meantime to obtain a more stable plasma and tissue levels and a constant therapeutic response. 76 parkinsonian patients were studied. Their L-dopa regimen was halved and 10 days after (-)deprenyl was added. After the decrease of L-dopa therapy a worsening of symptomatology was observed as expected. The association with (-)deprenyl was able to reverse this trend and when the inhibition of MAOB was really effective patients showed an improvement of symptoms even when compared to baseline values. No relevant side effects were observed and no patients dropped out.

Subcutaneous lisuride infusion in Parkinson's disease: clinical results using different modes of administration.

The continuous dopaminergic stimulation provided by infusion of dopamine agonist drugs, is a very effective strategy to control ON-OFF fluctuation in Parkinson's disease. Lisuride is a potent dopamine agonist drug, very soluble in water and can be administered subcutaneously. Many authors have shown that the subcutaneous infusion of lisuride can control fluctuations when applied in combination with oral levodopa as a 24 hour continuous infusion regimen. In this study, lisuride was given without any other antiparkinsonian medicament and using a 12 hour infusion regimen wherever possible. 13 fluctuating Parkinsonian patients were studied. 6 out of these 13 were satisfactory treated with lisuride alone and the remaining 7 with a combination of Lisuride + oral levodopa. Only in 3 out of 13 patients the 24 hour infusion regimen was required.

Antagonist effect of terguride in Parkinson's disease.

The effects of the partial dopamine agonist terguride (9,10 transdihydrolisuride; THDL) on striatal dopamine receptors were studied by its i.v. administration to 13 patients with Parkinson's disease. Patients were maintained in a steadily mobile state with abnormal involuntary movements by a constant i.v. infusion of levodopa. Terguride showed dopamine antagonist properties in nine patients. In two of these nine patients, a decrease in dyskinesia score was observed without a concomitant worsening of parkinsonian symptoms, whereas in the remaining seven, full parkinsonian akinesia followed THDL administration. The subsequent i.v. injection of the dopamine agonist lisuride reversed THDL-induced akinesia in these seven patients. In the remaining four patients, no clinically significant motor effects were observed. These results show dopamine antagonist activity of terguride in patients with Parkinson's disease treated with Levodopa. Further studies using a wider dose titration are required to evaluate the possible role of dopamine partial agonists in the therapy of levodopa-induced dyskinesias.

Short and valid assessment of apraxia in Parkinson's disease.

BACKGROUND: Valid assessment of apraxia in usually non-apraxic Parkinson's disease helps to delineate atypical parkinsonism frequently associated with apraxia. Furthermore, in a subgroup of late Parkinson's disease apraxia, typically the ideomotor subtype, may gradually superimpose onto parkinsonian motor symptoms contributing to defective manual skill. Here we evaluate the utility of a brief, standardized test, the apraxia screen of TULIA (AST). METHODS: Seventy five Parkinson's disease patients were tested with the AST. Parkinsonian motor deficits were measured using Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III and difficulties in activities of daily living (ADL) by modified MDS-UPDRS part II (eating, dressing, personal hygiene, and writing). RESULTS: No association was found between the AST and MDS-UPDRS part III, indicating that AST discriminates well (discriminative validity) between apraxia and parkinsonism. Furthermore, AST was associated with ADL and Hoehn & Yahr stage (convergent validity). CONCLUSIONS: AST is a short and valid test to rule out or detect apraxia in Parkinson's disease.

[Psychological and cognitive problems in Parkinson disease--therapeutic possibilities]. / Psychische und kognitive Probleme bei Morbus Parkinson--therapeutische Möglichkeiten.

Depression, hallucinations, psychosis and cognitive deficits may often complicate advanced Parkinson's disease. Their detection and treatment have extraordinary importance, as they may cause significant invalidity and even an increase in mortality. Optimization of antiparkinsonian therapy may exert a positive influence on depressive symptoms, and should therefore be performed before antidepressant drugs are started. On the other hand, hallucinations and dementia do usually benefit from a discontinuation or dosage reduction of anticholinergic drugs, selegiline, DA-agonists and amantadine. When a levodopa monotherapy is indicated, slow-release formulations should be avoided. When a neuroleptic treatment is needed, clozapine and maybe quetiapine should be preferred. Preliminary evidence suggests that cholinesterase inhibitors might partially improve cognitive deficits in Parkinson's disease.

Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease.

The management of fluctuations in motor function complicating advanced Parkinson's disease with continuously administered dopaminomimetics was studied in 12 patients. In response to 7 to 12 days of round-the-clock intravenous infusions of levodopa, fluctuations in motor performance gradually diminished, ultimately by more than 40%. The beneficial effect persisted for about 6 days after withdrawal of continuous parenteral treatment and resumption of standard oral therapy. Clinical improvement was associated with changes in several pharmacological indices: Acute dose-response studies of intravenous levodopa showed a shift of the curve to the right in the immediate postinfusion phase compared to preinfusion studies; the therapeutic index improved significantly as patients demonstrated about 76% increased beneficial antiparkinsonian response with an equal degree of toxic dyskinetic effects; and the duration of action of levodopa was prolonged by 30%. These results suggest that changes in central dopaminergic mechanisms contributing to motor complications in advanced Parkinson's disease can be modified by procedures that provide continuous dopamine replacement. Presumably these modifications underlie the gradual amelioration of motor fluctuations over several days of round-the-clock therapy. Results of the present study also suggest potential deleterious effects of chronic intermittent oral treatment in the development of motor complications and thus support the role of long-term, continuous administration of dopaminomimetics.

No evidence for altered muscle mitochondrial function in Parkinson's disease.

Recent reports indicate that reductions in mitochondrial respiratory chain function occur in substantia nigra, platelets, and muscle from patients with Parkinson's disease. To confirm and further characterise the presence of a generally distributed mitochondrial defect, mitochondrial metabolism was evaluated in muscle obtained from subjects with Parkinson's disease and from normal controls. Oxygen consumption rates in muscle mitochondria represented by complex I, complexes II-III, or complex IV did not differ between the two groups. Likewise, activities of rotenone sensitive NADH cytochrome c reductase, succinate cytochrome c reductase, or cytochrome oxidase in muscle mitochondria were not significantly different between Parkinsonian and control subjects. These findings fail to provide support for a generalised defect in mitochondrial function in Parkinson's disease but do not exclude an abnormality in respiratory function confined to the substantia nigra.

Comparison of the clinical pharmacology of (-)NPA and levodopa in Parkinson's disease.

Direct acting dopamine agonists are generally less effective than levodopa in relieving symptoms of Parkinson's disease. In an attempt to quantitate and explain this situation, the acute motor responses to intravenous injections of the dopamine agonist, (-)-N-n-propyl-norapomorphine hydrochloride (NPA), were compared with those of the dopamine precursor, levodopa. At optimum dose levels, the acute anti-Parkinsonian efficacy of NPA averaged only about 50% of maximum, while essentially total symptom suppression was obtained with levodopa in patients previously treated with the amine precursor. Dyskinesia severity, however, was similar with the two drugs. These differences in anti-Parkinsonian efficacy may reflect the fact that while NPA acts mainly on D-2 dopamine receptors, levodopa results in stimulation of both the D-1 and D-2 subsets of receptors at a more physiological ratio. Future efforts to develop dopamine agonists for the treatment of Parkinsonian symptoms may thus have to consider focusing on drugs having pharmacological profile more similar to that of dopamine.

Somatostatin replacement therapy for Alzheimer dementia.

Somatostatin is consistently diminished in brains of patients with Alzheimer's disease. To evaluate whether pharmacological restoration of this transmitter deficit has therapeutic value, the synthetic analogue octreotide was administered intravenously to 14 Alzheimer patients under double-blind, placebo-controlled conditions. At the highest dose administered, spinal fluid concentrations approximated those found in brains of experimental animals receiving behaviorally effective amounts of the drug. Neuropsychological testing, however, showed no clinically significant improvement. Coadministration of octreotide and physostigmine to 1 patient also failed to improve cognition. Positron emission tomographic studies in 6 patients revealed a generalized decrease in glucose metabolism as a result of octreotide infusion. These findings suggest that stimulation of the somatostatin system has no value in the symptomatic treatment of Alzheimer dementia.