Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease.

Alzheimer's disease (AD) has been genetically and pathologically associated with neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor involved in innate immunity. TREM2 rare protein coding genetic variants have been linked to AD. A soluble TREM2 (sTREM2) cleavage product is elevated in AD. It is unclear whether there is a relationship between elevated sTREM2 and markers of inflammation. The hypothesis of this investigation was that central and peripheral inflammation play a role in sTREM2 levels in AD. A consistent association of peripheral or central markers of inflammation and CSF sTREM2 levels was not found, suggesting a limited impact of general inflammation on sTREM2 levels. An association between peripheral sTREM2 levels and CSF sTREM2, as well as an association between CSF sTREM2 and a marker of blood brain barrier integrity, was observed in AD, suggesting a potential role of peripheral TREM2 in central TREM2 biology.

Incorporating a prediction of postgrazing herbage mass into a whole-farm model for pasture-based dairy systems.

The DairyNZ whole-farm model (WFM; DairyNZ, Hamilton, New Zealand) consists of a framework that links component models for animal, pastures, crops, and soils. The model was developed to assist with analysis and design of pasture-based farm systems. New (this work) and revised (e.g., cow, pasture, crops) component models can be added to the WFM, keeping the model flexible and up to date. Nevertheless, the WFM does not account for plant-animal relationships determining herbage-depletion dynamics. The user has to preset the maximum allowable level of herbage depletion [i.e., postgrazing herbage mass (residuals)] throughout the year. Because residuals have a direct effect on herbage regrowth, the WFM in its current form does not dynamically simulate the effect of grazing pressure on herbage depletion and consequent effect on herbage regrowth. The management of grazing pressure is a key component of pasture-based dairy systems. Thus, the main objective of the present work was to develop a new version of the WFM able to predict residuals, and thereby simulate related effects of grazing pressure dynamically at the farm scale. This objective was accomplished by incorporating a new component model into the WFM. This model represents plant-animal relationships, for example sward structure and herbage intake rate, and resulting level of herbage depletion. The sensitivity of the new version of the WFM was evaluated and then the new WFM was tested against an experimental data set previously used to evaluate the WFM and to illustrate the adequacy and improvement of the model development. Key outputs variables of the new version pertinent to this work (milk production, herbage dry matter intake, intake rate, harvesting efficiency, and residuals) responded acceptably to a range of input variables. The relative prediction errors for monthly and mean annual residual predictions were 20 and 5%, respectively. Monthly predictions of residuals had a line bias (1.5%), with a proportion of square root of mean square prediction error (RMSPE) due to random error of 97.5%. Predicted monthly herbage growth rates had a line bias of 2%, a proportion of RMSPE due to random error of 96%, and a concordance correlation coefficient of 0.87. Annual herbage production was predicted with an RMSPE of 531 (kg of herbage dry matter/ha per year), a line bias of 11%, a proportion of RMSPE due to random error of 80%, and relative prediction errors of 2%. Annual herbage dry matter intake per cow and hectare, both per year, were predicted with RMSPE, relative prediction error, and concordance correlation coefficient of 169 and 692kg of dry matter, 3 and 4%, and 0.91 and 0.87, respectively. These results indicate that predictions of the new WFM are relatively accurate and precise, with a conclusion that incorporating a plant-animal relationship model into the WFM allows for dynamic predictions of residuals and more realistic simulations of the effect of grazing pressure on herbage production and intake at the farm level without the intervention from the user.

Is 6 months of neuroleptic withdrawal sufficient to distinguish drug-induced parkinsonism from Parkinson's disease?

BACKGROUND: Drug-induced parkinsonism (DIP) is the second commonest cause of akinetic-rigid syndrome in the western world. Differentiating DIP from Parkinson's disease (PD) may be a challenge to clinicians. One of the factors distinguishing DIP from PD is that discontinuation of the neuroleptic agent in DIP should relieve the symptoms of parkinsonism. The majority of the literature uses the 6-month timeframe between the neuroleptic withdrawal and resolution of the symptoms of parkinsonism. METHODS: We report two cases of DIP wherein the symptoms of parkinsonism persisted more than 6-months from withdrawal of the dopamine receptor blocking agent (DRBA) and the results of their ioflupane iodine-123 (DaT) single-photon emission computed tomography (SPECT) scan. DaT scan is a newly approved radiopharmaceutical in the United States indicated for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. RESULTS: The first case is a patient who developed parkinsonism from risperidone, while the second case developed parkinsonism from metoclopramide. In both cases, parkinsonism persisted 6 months after discontinuation of the DRBA, therefore DaT scan was obtained, showing normal striatal dopamine transporter uptake. Nine months after the discontinuation of the DRBA, parkinsonism was significantly improved in both patients but not completely resolved. CONCLUSION: Our two cases illustrate the possibility of persistent parkinsonism beyond 6-9 months from the time of neuroleptic withdrawal without evidence of presynaptic dopaminergic neuronal loss that would be suggestive of conversion to PD. We recommend that the official recommendation of the minimum time of neuroleptic withdrawal be modified to at least 1 year before entertaining the diagnosis of PD conversion in patients with exposure to DRBAs.

A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease.

OBJECTIVE: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD). METHODS: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12. RESULTS: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function. CONCLUSIONS: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD.

Usefulness of screening tools for predicting driving performance in people with Parkinson's disease.

OBJECTIVE: We used screening tests administered by a certified driving rehabilitation specialist and by Parkinson's disease (PD) specialty neurologists to develop a model to predict on-road outcomes for patients with PD. METHOD: We administered a battery of screening tests to 41 patients with PD and 41 age-matched control participants before on-road testing. We used statistical models to predict actual on-road performance. RESULTS: The PD group had a higher failure rate, indicating more on-road errors. For the PD participants, the Useful Field of View (UFOV) Subtest 2 and Rapid Pace Walk were responsible for most of the variance in the on-road test. The model accurately categorized pass-fail outcomes for 81% of PD patients. CONCLUSION: Clinical screening batteries may be predictive of driving performance in PD. The UFOV Subtest 2, administered in approximately 15 min, may be the single most useful clinical test for such predictions.

Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson's disease.

Impulse-control disorders (ICDs) are becoming more commonly recognized in the Parkinson disease (PD) population. To date, there are no definitive methods of treating dopamine dysregulation syndromes in PD patients. We sought to uncover an effective treatment option for future study. We report a series of 3 PD patients with ICDs who were effectively treated with valproate. Based on these encouraging preliminary observations, future controlled clinical trials investigating the efficacy of valproate for ICDs in PD are recommended.

Levodopa-carbidopa intestinal gel for treatment of advanced Parkinson's disease.

BACKGROUND: Levodopa is the mainstay of Parkinson's disease (PD) treatment, but is often eventually associated with disabling motor complications in patients with advanced PD. The inability of perorally administered levodopa to provide more physiologic continuous dopaminergic stimulation (CDS) is a leading hypothesis to explain these complications. OBJECTIVE: To investigate the cumulative efficacy and safety, and re-evaluate the role, of levodopa-carbidopa intestinal gel (LCIG) infusion in treatment of advanced PD patients experiencing levodopa-associated motor complications, through its purported mechanism for providing CDS. METHODS: Literature searches in the MEDLINE/PubMed database were used to identify peer-reviewed publications examining the role of CDS in levodopa-associated motor complications and pharmacologic strategies for CDS, focusing on LCIG infusion for advanced PD patients. RESULTS: LCIG, an aqueous gel, is continuously infused (daytime only or 24 h) via a portable pump and tube permanently inserted into the duodenum through percutaneous endoscopic gastrostomy (PEG). LCIG infusion provides stable levodopa plasma levels, which are significantly less variable than those with oral levodopa. Clinical trials indicate LCIG may significantly improve motor complications (reduction of time in 'off' and time in 'on with dyskinesias'), motor scores using the Unified Parkinson's Disease Rating Scale (UPDRS), non-motor symptomatology (Non-motor Symptom Scale) and health-related quality of life (HRQOL) in advanced PD patients. The adverse-event profile of LCIG is similar to that of oral levodopa, although technical problems with the infusion device have occurred in up to 70% of patients. CONCLUSION: LCIG has demonstrated efficacy in reducing levodopa-associated motor complications in patients with advanced PD, and improving UPDRS and HRQOL scores. Because it involves PEG and its associated risks, LCIG is recommended for patients in whom motor fluctuations and dyskinesias are inadequately treated with traditional peroral medication. For these patients, LCIG can be a valuable alternative to deep brain stimulation (DBS), especially when DBS is contraindicated. These conclusions are limited by the modest number and size of completed randomized, controlled trials of LCIG.

Aspiration and swallowing in Parkinson disease and rehabilitation with EMST: a randomized trial.

OBJECTIVE: Dysphagia is the main cause of aspiration pneumonia and death in Parkinson disease (PD) with no established restorative behavioral treatment to date. Reduced swallow safety may be related to decreased elevation and excursion of the hyolaryngeal complex. Increased submental muscle force generation has been associated with expiratory muscle strength training (EMST) and subsequent increases in hyolaryngeal complex movement provide a strong rationale for its use as a dysphagia treatment. The current study's objective was to test the treatment outcome of a 4-week device-driven EMST program on swallow safety and define the physiologic mechanisms through measures of swallow timing and hyoid displacement. METHODS: This was a randomized, blinded, sham-controlled EMST trial performed at an academic center. Sixty participants with PD completed EMST, 4 weeks, 5 days per week, for 20 minutes per day, using a calibrated or sham, handheld device. Measures of swallow function including judgments of swallow safety (penetration-aspiration [PA] scale scores), swallow timing, and hyoid movement were made from videofluoroscopic images. RESULTS: No pretreatment group differences existed. The active treatment (EMST) group demonstrated improved swallow safety compared to the sham group as evidenced by improved PA scores. The EMST group demonstrated improvement of hyolaryngeal function during swallowing, findings not evident for the sham group. CONCLUSIONS: EMST may be a restorative treatment for dysphagia in those with PD. The mechanism may be explained by improved hyolaryngeal complex movement. CLASSIFICATION OF EVIDENCE: This intervention study provides Class I evidence that swallow safety as defined by PA score improved post EMST.

Mood and motor effects of thalamic deep brain stimulation surgery for essential tremor.

PURPOSE: The aim of this study was to evaluate the effects of unilateral and bilateral ventralis intermedius (Vim) deep brain stimulation (DBS) on mood and motor function. METHODS: Thirty-one consecutive medication refractory patients with essential tremor who underwent unilateral or bilateral Vim DBS at University of Florida and returned for at least 6 -month follow-up completed the Visual Analog Mood (VAMS), the Beck Depression Inventory (BDI), and the Tremor Rating Scale (TRS) before and after surgery. We excluded all patients who were implanted at other institutions. RESULTS: The tense subscale of the VAMS improved significantly in both the unilateral and bilateral DBS groups (P < 0.001). On the VAMS afraid subscale, only the bilateral group trended toward improvement (P = 0.075). There were no significant changes for either group for the happy, confused, sad, angry, energetic or tired VAMS scores. TRS subscale scores all improved after unilateral and bilateral Vim DBS surgery (P < 0.001). CONCLUSIONS: Feelings of tenseness, tremor severity and ADLs improved following unilateral or bilateral Vim DBS for ET.

Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial.

OBJECTIVE: 6002-US-051 was a 12-week, double-blind study evaluating the safety and efficacy of istradefylline, a selective A(2A) adenosine receptor antagonist, as monotherapy in patients with Parkinson's disease (PD). METHODS: Patients with Hoehn-Yahr stages 1-2.5 who had not received dopaminergic drugs in the past 30 days or levodopa for >30 days at anytime were randomized to 40 mg/day istradefylline or placebo. The primary efficacy outcome was the change from Baseline to Endpoint in the Unified Parkinson's Disease Rating Scale (UPDRS) Subscale III score. Safety was assessed by physical examination, laboratory tests, electrocardiograms, and adverse event monitoring. RESULTS: 176 patients comprised the intent-to-treat population. Although istradefylline showed numerically greater improvements in UPDRS Subscale III at each time point and reached statistical significance at Week 2 (LS mean difference = -1.47), it did not show statistically significant improvement from placebo for the primary endpoint (least square [LS] mean difference = -1.11). Similar proportions of patients in each group experienced treatment-emergent adverse events (63% istradefylline, 65% placebo). CONCLUSIONS: Istradefylline, as monotherapy in patients with PD, is safe and well tolerated. However, efficacy in improving motor symptoms in early PD was not statistically demonstrated by this study.

Useful field of view as a reliable screening measure of driving performance in people with Parkinson's disease: results of a pilot study.

PURPOSE: To determine the correlations of the Useful Field of View (UFOV), compared to other clinical tests of Parkinson's disease (PD); vision; and cognition with measures of on-road driving assessments and to quantify the UFOV's ability to indicate passing/failing an on-road test in people with PD. METHODS: Nineteen randomly selected people with idiopathic PD, mean age = 74.8 (6.1), 14 (73.7%) men, 18 (94.7%) Caucasians, were age-matched to 104 controls without PD. The controls had a mean age of 75.4 (6.4), 59 (56.7%) men, 96 (92.3%) Caucasians. Both groups were referred for a driving evaluation after institutional review board approval. RESULTS: Compared to neuropsychological and clinical tests of vision and cognition, the UFOV showed the strongest correlations (r > .75, p < 0.05) with measures of failing a standardized road test and number of driving errors. Among PD patients, the UFOV Risk Index score of 3 (range 1-5) was established as the optimal cutoff value for passing the on-road test, with sensitivity 87 percent and specificity 82 percent, AUC = 92 percent (SE 0.61, p = .002). Similarly, the UFOV 2 (divided attention) optimum cutoff value is 223 ms (range 16-500 ms), sensitivity 87.5 percent, specificity 81.8 percent, AUC = 91 percent (SE 0.73, p = .003). The UFOV 3 (selected attention) optimal cutoff value is 273 ms (range 16-500 ms), sensitivity 75 percent, specificity 72.7 percent, AUC = 87 percent (SE 0.81, p = .007). CONCLUSION: In this pilot study among PD patients, the UFOV may be a superior screening measure (compared to other measures of disease, cognition, and vision) for predicting on-road driving performance but its rigor must be verified in a larger sample of people with PD.

Perceptual characteristics of Parkinsonian speech: a comparison of the pharmacological effects of levodopa across speech and non-speech motor systems.

The purpose of this study was to: (1) define perceptual speech characteristics of idiopathic Parkinson disease (IPD) across 35 speech dimensions adapted from Darley et al. [19] and grouped under six speech-sign clusters (respiration, phonation, resonance, articulation, prosody and rate); (2) examine the effects of levodopa on the 35 perceptual speech dimensions and speech-sign clusters; and (3) to compare the relative effectiveness of levodopa on global motor functioning vs. speech production. Sixteen patients with IPD read the 'Grandfather Passage' both 'on' and 'off' levodopa. Three blinded speech-language pathologists performed perceptual speech analyses using a seven-point scale. The diagnosis of IPD was made by a movement disorders fellowship trained neurologist who applied UK Brain bank criteria and administered the Unified Parkinson Disease Rating Scale. Concordant with previous studies, the results of this experiment indicated that IPD disrupted multiple speech production subsystems, with prosody being the most severely affected domain. The perceptual dimensions that were most severely affected included: (1) sound imprecision; (2) mono-loudness; (3) mono-pitch; (4) reduced stress and (5) harsh voice. No significant differences were obtained between medicated states ('on'/'off') for any of the 35 individual speech dimensions and speech-sign clusters. Global motor function significantly improved following dopaminergic medications.

Brain penetration effects of microelectrodes and DBS leads in STN or GPi.

OBJECTIVE: To determine how intraoperative microelectrode recordings (MER) and intraoperative lead placement acutely influence tremor, rigidity, and bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead placement effects were influenced by target location (subthalamic nucleus (STN) or globus pallidus interna (GPi)). BACKGROUND: Currently most groups who perform deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as macrostimulation (test stimulation), to refine DBS lead position. Following MER and/or test stimulation, however, there may be a resultant "collision/implantation" or "microlesion" effect, thought to result from disruption of cells and/or fibres within the penetrated region. These effects have not been carefully quantified. METHODS: 47 consecutive patients with PD undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function was measured at six time points with a modified motor Unified Parkinson Disease Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3) immediately after lead implantation/collision, (4) 4 months following surgery-off medications, on DBS (12 h medication washout), (5) 6 months postoperatively-off medication and off DBS (12 h washout) and (6) 6 months-on medication and off DBS (12 h washout). RESULTS: Significant improvements in motor scores (p<0.05) (tremor, rigidity, bradykinesia) were observed as a result of MER and lead placement. The improvements were similar in magnitude to what was observed at 4 and 6 months post-DBS following programming and medication optimisation. When washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved compared with preoperative testing. There was a larger improvement in STN compared with GPi following MER (p<0.05) and a trend for significance following lead placement (p<0.08) but long term outcome was similar. CONCLUSION: This study demonstrated significant acute intraoperative penetration effects resulting from MER and lead placement/collision in PD. Clinicians rating patients in the operating suite should be aware of these effects, and should consider pre- and post-lead placement rating scales prior to activating DBS. The collision/implantation effects were greater intraoperatively with STN compared with GPi, and with greater disease duration there was a larger effect.

Subjective perception of cognition is related to mood and not performance.

OBJECTIVE: Clinicians monitor cognitive effects of drugs primarily by asking patients to describe their side effects. We examined the relationship of subjective perception of cognition to mood and objective cognitive performance in healthy volunteers and neurological patients. METHODS: Three separate experiments used healthy adults treated with lamotrigine (LTG) and topiramate (TPM), adults with epilepsy on LTG or TPM, and patients with idiopathic Parkinson's disease. Correlations were calculated for change scores on and off drugs in the first two experiments and for the single assessment in Experiment 3. RESULTS: Across all three experiments, significant correlations were more frequent (chi(2)=259, P < or = 0.000) for mood versus subjective cognitive perception (59%) compared with subjective versus objective cognition (2%) and mood versus objective cognitive performance (2%). CONCLUSIONS: Subjective perception of cognitive effects is related more to mood than objective performance. Clinicians should be aware of this relationship when assessing patients' cognitive complaints.

Does laterality of motor impairment tell us something about cognition in Parkinson disease?

This cross-sectional study investigates the relationship between severity of right- and left-sided motor symptoms and deficits in global cognitive function as well as individual cognitive domains in 117 Parkinson disease patients. Items of the Unified Parkinson Disease Rating Scale Part III were divided into right- and left-sided total scores. Composite scores in verbal fluency, verbal memory, executive function, and visuoperceptual skills were obtained from a full neuropsychological battery. We observed a significant association between right-sided motor impairment and verbal memory, visuoperceptual skills, and verbal fluency, but not executive function. The relationship between right symptoms and verbal fluency was fully mediated by cognitive status, while the relationship between right symptoms and verbal memory as well as visuoperceptual skills was not. Left-sided motor symptoms were not significantly related to any composite cognitive domain. When patients were divided into groups based on the side of predominant symptoms, no group differences were found in performance on the specific cognitive domains. This suggests that the degree of right-sided symptoms is more correlated to specific cognitive domains than is group classification of laterality.

BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups.

Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here.

Limb-kinetic apraxia in Parkinson disease.

To learn if limb-kinetic apraxia (LKA) is associated with Parkinson disease (PD), participants with PD (on medications) and control subjects performed finger tapping (FT), measuring movement speed, and performed coin rotation (CR), measuring precise coordinated but independent finger movements and speed. There were no group differences in FT, a measure of bradykinesia-rigidity, but CR rotation was impaired in PD. Thus, LKA, not related to bradykinesia-rigidity, is associated with PD.

LRRK2 mutations in a clinic-based cohort of Parkinson's disease.

In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2, encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202, controls: n = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD.

Dissociating apathy and depression in Parkinson disease.

OBJECTIVE: To examine the hypothesis that apathy is a core feature of Parkinson disease (PD) and that apathy can be dissociated from depression. METHODS: Eighty patients with PD and 20 patients with dystonia completed depression and apathy measures including the Marin Apathy Evaluation Scale (AES), Beck Depression Inventory (BDI), and Centers for Epidemiologic Studies-Depression Scale (CES-D). RESULTS: There was a significantly higher severity and frequency of apathy in PD (frequency = 51%, 41/80) than in dystonia (frequency = 20%, 4/20). Apathy in the absence of depression was frequent in PD and did not occur in dystonia (PD = 28.8%, dystonia = 0%). CONCLUSIONS: Patients with Parkinson disease (PD) experienced significantly higher frequency and severity of apathy when compared with patients with dystonia. Apathy may be a "core" feature of PD and occurs in the absence of depression.