The effect of dopamine therapy on ventral and dorsal striatum-mediated cognition in Parkinson\u27s disease: support from functional MRI.

The central aim of our study was to elucidate functions mediated by the ventral and dorsal striatum, respectively, to better understand the cognitive effects of dopamine replacement in Parkinson\u27s disease. We proposed that the ventral striatum underlies general learning of stimulus associations, whereas the dorsal striatum promotes integration of various influences on selecting. In Parkinson\u27s disease, dopamine depletion is substantially less notable in the ventral relative to the dorsal striatum, and therefore greater improvements are expected for dorsal striatum-mediated functions with dopamine replacement. Using a simple selection task, we found that dopamine replacement impaired encoding and facilitation of consistent stimulus-stimulus relations across trials. This finding was in line with our contention that ventral striatum mediates learning stimulus associations, even when explicit feedback or reward is not provided. In contrast, dopamine replacement enhanced interference related to assimilating conflicting influences on selection across trials, consistent with our hypothesis that the dorsal striatum supports deciding in ambiguous contexts. We further confirmed these separable roles for the ventral and dorsal striatum in our selection task with healthy young volunteers using functional magnetic resonance imaging. In summary, we present a within-subject, double dissociation of the effects of dopamine replacement in patients with Parkinson\u27s disease for ventral striatum-mediated facilitation and dorsal striatum-mediated interference, confirmed in a separate functional magnetic resonance imaging experiment. Defining the distinct functions of the ventral and dorsal striatum will have direct clinical implications. Titration of therapy in Parkinson\u27s disease is generally geared towards optimizing dorsal striatum-mediated motor symptoms, possibly at the expense of ventral striatum operations, a consequence that is only beginning to be recognized. Enhanced awareness of these different processes will translate into medication strategies that take into account those symptoms that dopamine replacement might hinder, as well as improve. Here, we show impairments in learning new stimulus associations compared with improvements in integrating varied influences related to selection. Ultimately, this knowledge will lead clinicians to survey a broader range of symptoms in determining optimal therapy based on individual patient priorities

Differential effects of Parkinson\u27s disease and dopamine replacement on memory encoding and retrieval.

Increasingly memory deficits are recognized in Parkinson\u27s disease (PD). In PD, the dopamine-producing cells of the substantia nigra (SN) are significantly degenerated whereas those in the ventral tegmental area (VTA) are relatively spared. Dopamine-replacement medication improves cognitive processes that implicate the SN-innervated dorsal striatum but is thought to impair those that depend upon the VTA-supplied ventral striatum, limbic and prefrontal cortices. Our aim was to examine memory encoding and retrieval in PD and how they are affected by dopamine replacement. Twenty-nine PD patients performed the Rey Auditory Verbal Learning Test (RAVLT) and a non-verbal analogue, the Aggie Figures Learning Test (AFLT), both on and off dopaminergic medications. Twenty-seven, age-matched controls also performed these memory tests twice and their data were analyzed to correspond to the ON-OFF order of the PD patients to whom they were matched. We contrasted measures that emphasized with those that accentuated retrieval and investigated the effect of PD and dopamine-replacement on these processes separately. For PD patients relative to controls, encoding performance was normal in the off state and was impaired on dopaminergic medication. Retrieval was impaired off medication and improved by dopamine repletion. This pattern of findings suggests that VTA-innervated brain regions such as ventral striatum, limbic and prefrontal cortices are implicated in encoding, whereas the SN-supplied dorsal striatum mediates retrieval. Understanding this pattern of spared functions and deficits in PD, and the effect of dopamine replacement on these distinct memory processes, should prompt closer scrutiny of patients\u27 cognitive complaints to inform titration of dopamine replacement dosages along with motor symptoms

Examining dorsal striatum in cognitive effort using Parkinson\u27s disease and fMRI.

OBJECTIVE: Understanding cognition mediated by the striatum can clarify cognitive deficits in Parkinson\u27s disease (PD). Previously, we claimed that dorsal striatum (DS) mediates cognitive flexibility. To refute the possibility that variation in cognitive effort confounded our observations, we reexamined our data to dissociate cognitive flexibility from effort. PD provides a model for exploring DS-mediated functions. In PD, dopamine-producing cells supplying DS are significantly degenerated. DS-mediated functions are impaired off and improved on dopamine replacement medication. Functional magnetic resonance imaging (fMRI) can confirm striatum-mediated functions. METHODS: Twenty-two PD patients, off-on dopaminergic medication, and 22 healthy age-matched controls performed a number selection task. Numerical distance between number pairs varied systematically. Selecting between two numbers that are closer versus distant in magnitude is more effortful: the symbolic distance effect. However, selecting between closer versus distant number pairs is equivalent in the need to alter attention or response strategies (i.e., cognitive flexibility). In Experiment 2, 28 healthy participants performed the same task with simultaneous measurement of brain activity with fMRI. RESULTS: The symbolic distance effect was equivalent for PD versus control participants and across medication sessions. Furthermore, symbolic distance did not correlate with DS activation using fMRI. In this dataset, we showed previously that integrating conflicting influences on decision making is (1) impaired in PD and improved by dopaminergic therapy and (2) associated with preferential DS activation using fMRI. INTERPRETATION: These findings support the notion that DS mediates cognitive flexibility specifically, not merely cognitive effort, accounting for some cognitive deficits in PD and informing treatment

SLC6A3 polymorphism predisposes to dopamine overdose in Parkinson\u27s disease

In Parkinson\u27s disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients

Can a Trained Radiology Technician Do Arterial Obstruction Quantification in Patients With Acute Pulmonary Embolism?

Objectives: To assess interobserver variability between a trained radiology technician (RT) and an experienced radiologist in arterial obstruction quantification using the Qanadli obstruction index (QOI), in patients diagnosed with acute pulmonary embolism (APE) at CT pulmonary angiography (CTPA). Materials and Methods: A RT and a radiologist independently reviewed CTPAs of 97 consecutive, prospectively enrolled patients with APE, and calculated the QOI. They classified patients into three risk categories: high for QOI ≥40%, intermediate for QOI 20-37.5%, low for QOI <20%. Interobserver variability was investigated for QOI as a continuous variable and as a categorical variable (high, intermediate, and low-risk groups). Results: Mean QOI (±SD) was 39.5 ± 24.3% and 38.6 ± 18.9% for the RT and the radiologist, respectively. The mean QOI was not statistically different between the RT and the radiologist (p = 0.502), and the interobserver agreement was excellent (ICC = 0.905). The RT classified 54 patients (55.7%) as high, 17 (17.53%) as intermediate, and 26 (26.8%) as low risk. The radiologist classified 55 patients (56.7%) as high, 22 (22.7%) as intermediate, and 20 (20.6%) as low risk. The interrater agreement for risk stratification was excellent (weighted kappa = 0.844). Conclusion: Once the diagnosis of APE was established, an adequately trained RT achieved an accuracy comparable to that of an experienced radiologist regarding QOI calculation and risk assessment

SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease

In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients

Interobserver Agreement between On-Call Radiology Resident and General Radiologist Interpretations of CT Pulmonary Angiograms and CT Venograms

Acute pulmonary embolism (PE) has long been recognized as a life-threatening emergency, and although the statistics vary widely depending on the clinical setting, associated mortality rates have been estimated at 100 000 deaths per year in the United States, including 15% of in-hospital deaths. Consequently, the ability to obtain rapid and accurate diagnosis of PE becomes critical for clinical management, namely, early initiation of anticoagulant therapy. Current clinical practice algorithms advocate use of computed tomographic pulmonary angiogram (CTPA) to reliably diagnose or exclude PE. Most commonly, PE results from deep venous thrombosis (DVT). Therefore, in addition to the diagnosis of PE, the evaluation of the lower limbs in order to detect the presence of DVT is important for appropriate patient management. Although DVT can be diagnosed or excluded via sonographic evaluation of the lower limbs with Doppler technique, the use of combined CTPA and computed tomographic venogram (CTV) for one-time imaging allows diagnosing both PE and DVT

Interobserver Agreement between On-Call Radiology Resident and General Radiologist Interpretations of CT Pulmonary Angiograms and CT Venograms

<div><p>Objectives</p><p>To evaluate the interobserver agreement (IOA) between the initial radiology resident and the final staff radiologist reports of combined computed tomographic pulmonary angiograms (CTPA) and computed tomographic venograms (CTV) performed during on-call hours.</p><p>Materials and Methods</p><p>Approval by the institutional review board was obtained. Six-hundred and ninety-six consecutive studies (CTPA or CTPA with CTV) performed during on-call hours and interpreted by 30 residents were identified. Radiology residents’ reports were compared to the final staff reports. Three tests outcomes were considered (positive, P; negative, N; indeterminate, I). Discordant cases were reviews by a chest radiologist.</p><p>Results</p><p>CTPAs were reported by staff radiologists as positive for pulmonary embolism (PE) in 18% (126/694), with a kappa of 0.81 (95% CI 0.77-0.86) with 3 outcomes (P, N, I), and a kappa of 0.89 (95% CI 0.85-0.94) with 2 outcomes (P, N). Regarding PE location, good concordance was observed for positive studies, with a kappa of 0.86 (95% CI 0.78 – 0.95). CTVs were reported as positive by staff radiologists in 8.5% (33/388), with a kappa of 0.66 (95% CI 0.55-0.77) with 3 outcomes (P, N, I), and a kappa of 0.89 (95% CI 0.8-1.0) with 2 outcomes (P, N). The IOA between residents and staff radiologists increased with increasing residency year level for CTPAs, but did not for CTVs.</p><p>Conclusions</p><p>Very good and good IOA were observed between resident and staff radiologist interpretations for CTPA and CTV, respectively, with tendency towards improved IOA as residency level of training increased for CTPA, but not for CTV.</p></div

Agreement between resident and staff radiologists according to the year of residency for PE and DVT diagnosis for the 3 outcomes (Positive, Negative, Indeterminate).

<p>Agreement between resident and staff radiologists according to the year of residency for PE and DVT diagnosis for the 3 outcomes (Positive, Negative, Indeterminate).</p

Parkinson\u27s disease duration determines effect of dopaminergic therapy on ventral striatum function.

We investigated the hypothesis that variation in endogenous dopamine (DA) across brain regions explains dissimilar effects of dopaminergic therapy on aspects of cognition in early Parkinson\u27s disease (PD). Extensive degeneration of DA-producing cells in the substantia nigra cause dorsal striatum (DS) DA deficiency and movement abnormalities. Particularly in early PD, this contrasts with relative sparing of the dopaminergic cells of the ventral tegmental area (VTA). The hypothesis predicts that DS-mediated cognitive functions are deficient at baseline and improved by DA replacement, whereas functions depending upon VTA-innervated brain regions are normal off medication and worsen with treatment. The latter pattern presumably owes to overdose of relatively DA-replete VTA-supplied brain regions with medication levels titrated to DS-mediated motor symptoms. As PD progresses, however, VTA degeneration increases. Impairment in cognitive operations performed by VTA-innervated brain regions, such as the ventral striatum (VS), is expected. We compared the performance of early and late PD patients, on and off dopaminergic medication, relative to age-matched controls, on reward learning, previously shown to implicate the VS. As expected, in early PD, stimulus-reward learning was normal off medication, but worsened with DA replacement. At more advanced disease stages, PD patients learned stimulus-reward contingencies more poorly than controls and early PD patients off medication. Furthermore, dopaminergic medication did not worsen reward learning in late PD patients, in line with the dopamine overdose hypothesis. Unlike its effect on DS-mediated functions, however, DA-replacement therapy did not improve reward learning in late PD patients