The metabolic anatomy of tremor in Parkinson's disease

OBJECTIVE: To identify regional metabolic brain networks related specifically to the presence of tremor in PD. BACKGROUND: The pathophysiology of parkinsonian tremor is unknown. Because tremor in PD occurs mainly in repose, we used resting state PET with 18F-fluorodeoxyglucose (FDG) to identify specific metabolic brain networks associated with this clinical manifestation. METHODS: We studied two discrete groups of eight PD patients with and without tremor using FDG/PET. Both patient groups were matched for gender, age, and Unified Parkinson Disease Rating Scale ratings for akinesia and rigidity. Ten normal volunteer subjects served as controls. RESULTS: Network analysis with the Scaled Subprofile Model was performed in two steps. 1) We computed the expression of the PD-related pattern (PDRP) identified by us previously in each of the PD patients and control subjects. Although PDRP subject scores were abnormally elevated in the combined PD cohort (p < 0.005), these values did not differ in the PD patient groups with and without tremor (p = 0.36). 2) We used SSM to analyze the data from the combined PD cohort comprising both patient groups. We found that PD patients with tremor were characterized by increased expression of a metabolic network comprising the thalamus, pons, and premotor cortical regions. Subject scores for this pattern were elevated in the tremor group compared with the atremulous patient group and the normal control group (p < 0.005). CONCLUSIONS: The findings suggest that PD patients with tremor are characterized by distinct increases in the functional activity of thalamo-motor cortical projections. Modulation of this functional anatomic pathway is likely to be the mechanism for successful interventions for the relief of parkinsonian tremor.     

Levodopa does not aggravate postural tremor in Parkinson's disease

Characterization of postural tremor in Parkinson's disease (PD) is incomplete. It was suggested to be an exaggerated physiological tremor and to be enhanced by the action of levodopa. We compared the magnitude of postural tremor to the magnitude of rest tremor and to plasma levodopa levels in 20 PD patients, 10 with stable motor response to oral levodopa, and 10 with the wearing-off phenomenon. Tremor assessment included motor scores of the Unified Parkinson's Disease Rating Scale and accelerometric measurements. Accelerometric data showed that the absolute power of both rest and postural basal dominant tremor frequencies significantly diminished with the increase in plasma levodopa levels and increased with their decrease. Tremor frequencies were also significantly changed by levodopa, which slowed rest tremor and increased postural tremor dominant frequency. This latter, however, did not reach the 8- to 12-Hz frequency band said to be typical of exaggerated physiological tremor. No significant differences between groups were found in their tremor response to levodopa. This study shows that the net postural tremor exhibited by PD patients is improved by levodopa, that levodopa does not augment tremor in the 8- to 12-Hz range, and that this effect is independent of the patient's motor response pattern of oral levodopa.     

123I]beta-CIT and SPECT in essential tremor and Parkinson's disease

Resting and postural tremor may occur in essential tremor (ET) and Parkinson's disease (PD). The aim of the present study was to investigate the cocaine derivative [123I]beta-CIT, which labels striatal dopamine transporters, and SPECT in differentiating these diseases. METHODS: 30 healthy volunteers, 32 patients with ET and 29 patients with idiopathic PD of Hoehn/Yahr stage I were investigated. Specific over nondisplaceable binding ratios (target/cerebellum-1) were calculated for the striatum, the caudate nucleus and the putamen separately as well as a ratio putamen/caudate and the percent deviation of each patient's ratio from age-expected control values. RESULTS: Striatal [123I]beta-CIT binding ratios in ET were within normal ranges and showed only a discrete elevation to age-expected control values (+14.6%). In PD significantly reduced specific binding was evident not only contralaterally to the clinically affected side (putamen: -62%, caudate nucleus: -35%), but also ipsilaterally (putamen: -45%, caudate nucleus: -22%). All investigated parameters differed significantly between PD and controls and ET respectively. CONCLUSION: Imaging striatal dopamine transporters with [123I]beta-CIT and SPECT could clearly distinguish between ET and PD in an early stage of the disease. Findings do not suggest a subclinical involvement of dopaminergic nigrostriatal neurons in ET.     

Effects of SR 141716A after acute or chronic cannabinoid administration in dogs

This study was undertaken to investigate the effects induced by the systemic administration of RB 101 [N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxoprpyl]-L-phenylalanine benzyl ester], a mixed inhibitor of the enkephalin catabolism able to cross the blood-brain barrier, in antinociception produced by adrenal medullary tissue transplanted in the rat spinal subarachnoid space. For this purpose, the antinociceptive responses induced by intravenous (i.v.) administration of RB 101 were evaluated in the tail-flick in rats transplanted 28 and 56 days before the test. Systemic administration of RB 101 induced antinociceptive effects in sham-operated rats, as previously reported. RB 101 also enhanced significantly the antinociception produced by the autotransplant 28 and 56 days after surgery. The antinociceptive responses of RB 101 in both sham-operated and autotransplanted rats were blocked by naloxone, but were not modified by the noradrenergic antagonist, phentolamine, suggesting a selective involvement of opioid mechanisms. The present results indicate that the inhibitors of enkephalin catabolism enhance the antinociception induced by adrenal medullary transplants.     

Drug administration in chronic liver disease

Cirrhosis encompasses a range of pathophysiological changes that may alter drug disposition. Drugs that are dependent primarily on the liver for their systemic clearance are more likely to be subject to reduced elimination and subsequent accumulation. Drug accumulation may lead to excessive plasma drug concentrations and adverse effects, if the adverse effects of the drug are concentration-dependent. The effects of hepatic insufficiency on the pharmacokinetics of drugs are not consistent or predictable. Furthermore, the influence of hepatic disease on the disposition of various drugs can vary, even though those drugs may share the same apparent metabolic pathway. Problems in forecasting drug kinetic behaviour are further enhanced by the additional impairment of kidney function (frequently encountered in patients with advanced liver disease) and by the unpredictability of the glomerular filtration rate using customary methods in patients with cirrhosis. Accordingly, dosages are generally adapted empirically, with the help of serum drug concentrations, when applicable. However, drugs eliminated predominantly by hepatic metabolism are not among those most commonly inducing adverse drug reactions or causing severe complications in patients with cirrhosis. Electrolyte disturbances and the hepatorenal syndrome produced by furosemide (frusemide)-the disposition of which is not substantially modified in liver disease-appear to be the most frequent adverse drug reactions in patients with liver disease. Furthermore, clinically significant alterations in the action of medications at concentrations generally considered to be in the normal therapeutic range are not uncommon. Tissue responsiveness to the pharmacological action of some drugs may be modified, as evidenced by the increased susceptibility of the brain in patients with cirrhosis to the action of many psychoactive agents. Another example is the greater susceptibility of such patients to the nephrotoxic potential of aminogly-cosides, which should not be used in this patient group. Drugs may also interfere with adaptive physiological processes induced by liver disease. ACE inhibitors and nonsteroidal anti-inflammatory drugs counteract the enhanced activity of the renin-angiotensin system in advanced liver disease, thereby generating a high risk of excessive hypotension or acute renal failure, respectively. These drugs are best avoided in patients with cirrhosis. Finally, there may be pharmacological effects that overlap with some pathophysiological modifications related to the process of liver disease, such as increased portal pressure produced by some calcium antagonists, or hypoprothrombinaemia related to the inhibition of synthesis of vitamin K-dependent clotting factors by some beta-lactam antibacterials (especially moxalactam and cefamandole). Accordingly, the use of these drugs should be avoided in advanced liver disease. It is noteworthy that reduced drug metabolism in patients with liver disease does not seem to have a significant impact on the frequency of hepatotoxicity. Special caution should be exercised, however, in patients with alcoholic liver disease because excessive alcohol intake may potentiate the hepatotoxic effect of paracetamol (acetaminophen).     

Effects of acute caffeine administration on adolescents.

Acute caffeine administration has physiological, behavioral, and subjective effects. Despite its widespread use, few studies have described the impact of caffeine consumption in children and adolescents. The purpose of this study was to investigate the effects of acute caffeine administration in adolescents. We measured cardiovascular responses and snack food intake after acute administration of 0 mg, 50 mg, 100 mg, and 200 mg of caffeine. We also compared usual food intake and subjective effects of caffeine between high- and low-caffeine consumers. Finally, we conducted a detailed analysis of caffeine sources and consumption levels. We found main effects of caffeine dose on heart rate (HR) and diastolic blood pressure (DBP), with HR decreasing and DBP increasing with increasing caffeine dose. There were significant interactions among gender, caffeine use, and time on DBP. High caffeine consumers (>50 mg/day) reported using caffeine to stay awake and drinking coffee, tea, soda, and energy drinks more than low consumers (     

Parkinson's disease: The psychological aspects of a chronic illness.

In a review of the literature on the psychological and social aspects of Parkinson's disease, it is noted that since the discovery of the underlying neuropathology of parkinsonism, research on its psychological aspects has had a biomedical orientation and has focused almost exclusively on the depression and cognitive impairment observed in a substantial proportion of Parkinson's patients. Present evidence does not permit firm conclusions about the relative contributions of neurological and psychosocial factors to these symptoms. Methodological problems, reliance on indirect evidence, and the paucity of psychosocial data all contribute to the inconclusiveness of the findings. It is argued that a comprehensive understanding of the psychological aspects of Parkinson's disease depends on combining the investigation of how individual patients experience and adapt to their illness with the prevailing biomedical approach to research. (117 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of acute and chronic dieldrin administration on liver and plasma esterases of the rat

A heritable propensity to develop malignant lesions is found in individuals with familial adenomatosis of the colon an rectum (ACR) and the Gardner's syndrome variant, an autosomal dominant trait. In the present study, the growth characteristics of cultured skin fibroblasts (SF) derived from normal-appearing flat skin biopsies of ACR families, representing all phenotypes, and appropriate controls were investigated. SF were obtained from stocks between the second and fifth passages and growth to confluency in Eagle's Minimal Essential Medium (EMEM) supplemented with 15% fetal calf serum (FCS). Following trypsinization, cells were replanted in EMEM supplemented with either 1% or 15% FCS at an initial density of 4 x 10(3) cells/cm2 and counted daily for five days. Normal SF representing several age groups (both sexes) and those obtained from non-afflicted individuals of ACR families grew only in 15% FCS. In contrast, SF from ACR subjects and from embryonal skin grew both in 1% and 15% FCS. SF from several clinically asymptomatic adults, children or ACR patients, grew in 1% FCS as well. Cell cultures from ACR individuals showed regions of criss-crossed arrays and multilayered pattern. These growth properties were not observed in normal cell cultures. The SF from ACR individuals did not grow in methocel, nor did they form tumors in athymic mice. These results suggest the occurrence of previously undetected biochemical alterations in SF taken from ACR genotypes.     

Modulation of postural tremors at the wrist by supramaximal electrical median nerve shocks in essential tremor, Parkinson's disease and normal subjects mimicking tremor

The response of postural wrist tremors to supramaximal median nerve stimulation was examined in patients with hereditary essential tremor (n = 10) and Parkinson's disease (n = 9), and in normal subjects mimicking wrist tremor (n = 8). The average frequency of on-going tremor was the same in all three groups. Supramaximal peripheral nerve shocks inhibited and then synchronised the rhythmic electromyographic (EMG) activity of all types of tremor. The duration of inhibition ranged from 90 to 210ms, varying inversely with the frequency of on-going tremor. There was no significant difference in mean duration of inhibition or in the timing of the first peak after stimulation on the average rectified EMG records between the three groups. The degree to which supramaximal peripheral nerve shocks could modulate the timing of rhythmic EMG bursts in the forearm flexor muscles was also quantified by deriving a resetting index. No significant difference in mean resetting index of the three groups was found. These results suggest that such studies cannot be used to differentiate between the common causes of postural wrist tremors.     

Effects of acute progesterone administration upon responses to acute psychosocial stress in men.

Animal studies suggest that neuroactive steroids, in particular progesterone and its metabolites, have stress-dampening effects. However, few studies have explored these effects in humans. In this study, we investigated the effects of acute progesterone administration on responses to the Trier Social Stress Test (TSST). Healthy men participated in the TSST 3.5 hrs after intramuscular injection of 0, 50, or 100 mg progesterone (N = 16, 14, and 14). We measured cardiovascular (heart rate, blood pressure), hormonal (plasma adrenocorticotrophic hormone, cortisol, and noradrenaline), and subjective (e.g., anxiety, arousal) responses to stress in the three groups. Before the TSST, progesterone injections increased plasma levels without altering physiological or subjective states. Stress produced its expected physiological and subjective effects among placebo-treated individuals. Progesterone 50 mg attenuated peak increases in plasma cortisol and reduced changes in negative mood and alertness after stress, yet it increased plasma noradrenaline and systolic blood pressure. Progesterone 100 mg also attenuated stress-induced increases in alertness and arousal, yet it potentiated stress-induced increases in diastolic pressure. Thus, progesterone dampened some of the psychological effects of stress but produced inconsistent effects on physiological stress responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Aortic regurgitation. Identifying and treating acute and chronic disease

Aortic regurgitation is a serious disorder that can challenge the best clinicians in terms of both diagnosis and management. The chronic form requires valve replacement when patients have symptoms or show evidence of left ventricular dysfunction. The acute form requires urgent aortic valve replacement. In all cases, medical management is only a temporizing procedure that can potentially mask the progression of left ventricular dysfunction. Endocarditis prophylaxis for indicated procedures is mandatory for all patients.     

Biological consequences of drug administration: Implications for acute and chronic tolerance.

The authors presented a model that extrapolates the biological consequences of drug administration to account for acute and chronic tolerance. Drug-induced changes of regulated parameters provide detectable perturbations to which the brain responds. With experience, these centrally mediated responses are learned and can be activated in the absence of the drug-induced perturbation. Although neural responses following drug administration are often obscured, the model shows how these responses may be identified and provides a reinterpretation of drug conditioning paradigms. The authors made comparisons between the present empirical model of drug administration and existing theories of drug tolerance. The authors also presented a unified framework for understanding the consequences of repeated drug use and made specific predictions as to the relationships among acute and chronic tolerance, drug sensitization, and individual differences in vulnerability to drug addiction. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Verb learning in Parkinson's disease.

The relative roles of grammatical processing and memory in the language comprehension difficulties of patients with Parkinson's disease (PD) were evaluated. 20 PD patients who did not have dementia were exposed to a new verb in a naturalistic setting. After 10 min, the semantic and grammatical information that they learned about the new verb was probed. Significant impairments in recalling some aspect of the new verb were seen in 55% of PD patients. Most of these patients demonstrated a language-sensitive deficit in appreciating grammatical information represented in the new verb. A small number of PD patients responded randomly to probes of all information about the new word, which suggests a memory impairment. It is concluded that difficulty in appreciating grammatical information contributes to the language impairments of PD patients. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metamemory and prospective memory in Parkinson's disease.

Objective: Metamemory is integral for strategizing about memory intentions. This study investigated the prospective memory (PM) deficit in Parkinson's disease (PD) from a metamemory viewpoint, with the aim of examining whether metamemory deficits might contribute to PM deficits in PD. Method: Sixteen patients with PD and 16 healthy older adult controls completed a time-based PM task (initiating a key press at two specified times during an ongoing task), and an event-based PM task (initiating a key press in response to animal words during an ongoing task). To measure metamemory participants were asked to predict and postdict their memory performance before and after completing the tasks, as well as complete a self-report questionnaire regarding their everyday memory function. Results: The PD group had no impairment, relative to controls, on the event-based task, but had prospective (initiating the key press) and retrospective (recalling the instructions) impairments on the time-based task. The PD group also had metamemory impairments on the time-based task; they were inaccurate at predicting their performance before doing the task but, became accurate when making postdictions. This suggests impaired metamemory knowledge but preserved metamemory monitoring. There were no group differences regarding PD patients' self-reported PM performance on the questionnaire. Conclusions: These results reinforce previous findings that PM impairments in PD are dependent on task type. Several accounts of PM failures in time-based tasks are presented, in particular, ways in which mnemonic and metacognitive deficits may contribute to the difficulties observed on the time-based task. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Intellectual and cognitive functions in Parkinson's disease.

Compared the performance of 25 parkinson's disease patients and 25 normals matched for age, race, sex, and education on 32 behavioral variables including the wechsler-bellevue intelligence scale (form i), halstead neuropsychological battery, and R. Reitan's trail making test. Ss with parkinson's disease had lower mean scores than controls on all 32 measures. Statistical comparisons indicated these differences were significant beyond the .001 level for 25 tests, and on only 1 measure was the probability level greater than .05. Results indicate that parkinson's disease patients have suffered marked deterioration not only in motor abilities but also in problem-solving, sensory, memory, general cognitive, and abstracting and organizing abilities. (23 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Working memory in mild Alzheimer's disease and early Parkinson's disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) impair working memory (WM). It is unclear, however, whether the deficits seen early in the course of these diseases are similar. To address this issue, the authors compared the performance of 22 patients with mild AD, 20 patients with early PD and without dementia, and 112 control participants on tests of inhibition, short-term memory, and 2 commonly administered tests of WM. The results suggest that although mild AD and early PD both impair WM, the deficits may be related to the interruption of different processes that contribute to WM performance. Early PD disrupted inhibitory processes, whereas mild AD did not. The WM deficits seen in patients with AD may be secondary to deficits in other cognitive capacities, including semantic memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Verbal learning strategies in Parkinson's disease.

Word-list learning was studied in patients with Parkinson's disease (PD) and normal control (NC) participants by means of the selective-reminding procedure of H. Buschke and P. A. Fuld (1974) in 3 learning conditions using semantically unrelated items; semantically related items, whose implicit categorical structure had to be spontaneously guessed; and semantically related items, whose explicit categorical structure was known in advance. The PD patients displayed poor learning in all 3 conditions. To identify the functional locus of the PD patients' deficits, the authors performed a stochastic Markov chain analysis, which allowed individual measurements of encoding, retrieval, and category clustering abilities. PD patients were never significantly impaired in encoding word engrams; their impairment was confined to automatic and intentional retrieval and to the ability to benefit from explicit semantic clues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Category learning deficits in Parkinson's disease.

Sixteen patients with Parkinson's disease (PD), 15 older controls (OCs), and 109 younger controls (YCs) were compared in 2 category-learning tasks. Participants attempted to assign colored geometric figures to 1 of 2 categories. In rule-based tasks, category membership was defined by an explicit rule that was easy to verbalize, whereas in information-integration tasks, there was no salient verbal rule and accuracy was maximized only if information from 3 stimulus components was integrated at some predecisional stage. The YCs performed the best on both tasks. The PD patients were highly impaired compared with the OCs, in the rule-based categorization task but were not different from the OCs in the information-integration task. These results support the hypothesis that learning in these 2 tasks is mediated by functionally separate systems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhanced negative priming in Parkinson's disease.

In the ignored repetition paradigm, negative priming (NP) is defined as the increase in response time that occurs when the current target stimulus served as a distractor stimulus in the previous trial. In this study, 25 Parkinson's disease (PD) participants and 17 age-matched healthy controls (HCs) were tested using a touchscreen version of the ignored repetition task that allowed response time to be partitioned into response initiation and response execution segments. In both groups, NP effects were stronger in the response execution than in the response initiation segments. The most striking result was that the PD group showed larger NP effects overall than the HC group. In PD, clinical ratings of bradykinesia, but not tremor, were related to larger NP effects. Results indicate that in PD, disruption of dopamine neuromodulation diminishes response efficiency when action must be directed toward previously ignored information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Visual construction impairments in Parkinson's disease.

24 nondemented Parkinson's disease (PD) patients were asked to copy and then recall the Rey-Osterrieth Complex Figure, dividing the units of the figure into "main structural" and "detail" components. PD patients consistently omitted some main structural units from recall of the figure. When main structures were produced, PD patients were impaired at drawing these features in an organized fashion, and they produced these main units late in the course of their drawings. PD patients differed from control Ss in their recall of the figure's details, but there were no qualitatively unique features in their omission of details. Correlation and regression analyses suggest that compromised executive functioning contributed to the PD patients' constructional difficulties and that visual perception and motor functioning also played a modest role. It is concluded that visual construction impairments in PD are multifactorial in nature. (PsycINFO Database Record (c) 2010 APA, all rights reserved)