Revisiting the Logan plot to account for non-negligible blood volume in brain tissue.

BACKGROUND: Reference tissue-based quantification of brain PET data does not typically include correction for signal originating from blood vessels, which is known to result in biased outcome measures. The bias extent depends on the amount of radioactivity in the blood vessels. In this study, we seek to revisit the well-established Logan plot and derive alternative formulations that provide estimation of distribution volume ratios (DVRs) that are corrected for the signal originating from the vasculature. RESULTS: New expressions for the Logan plot based on arterial input function and reference tissue were derived, which included explicit terms for whole blood radioactivity. The new methods were evaluated using PET data acquired using [11C]raclopride and [18F]MNI-659. The two-tissue compartment model (2TCM), with which signal originating from blood can be explicitly modeled, was used as a gold standard. DVR values obtained for [11C]raclopride using the either blood-based or reference tissue-based Logan plot were systematically underestimated compared to 2TCM, and for [18F]MNI-659, a proportionality bias was observed, i.e., the bias varied across regions. The biases disappeared when optimal blood-signal correction was used for respective tracer, although for the case of [18F]MNI-659 a small but systematic overestimation of DVR was still observed. CONCLUSIONS: The new method appears to remove the bias introduced due to absence of correction for blood volume in regular graphical analysis and can be considered in clinical studies. Further studies are however required to derive a generic mapping between plasma and whole-blood radioactivity levels.

Costs of illness and care in Parkinson's disease: an evaluation in six countries.

We investigated the costs of Parkinson's Disease (PD) in 486 patients based on a survey conducted in six countries. Economic data were collected over a 6-month period and presented from the societal perspective. The total mean costs per patient ranged from EUR 2620 to EUR 9820. Direct costs totalled about 60% to 70% and indirect costs about 30% to 40% of total costs. The proportions of costs components of PD vary notably; variations were due to differences in country-specific health system characteristics, macro economic conditions, as well as frequencies of resource use and price differences. However, inpatient care, long-term care and medication were identified as the major expenditures in the investigated countries.

Biomarkers for Alzheimer's disease therapeutic trials.

The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials.

Anxiety rating scales in Parkinson's disease: critique and recommendations.

Anxiety syndromes are common in patients with Parkinson's disease (PD) with up to 30% suffering from panic disorder, and up to 11% from generalized anxiety disorder (GAD). Anxiety is associated with increased subjective motor symptoms, more severe gait problems, dyskinesias, freezing, and on/off fluctuations. Anxiety has a negative impact on health related quality of life and is strongly associated with depressive syndromes. Since a variety of anxiety scales have been used in PD patients, the Movement Disorder Society commissioned a task force to assess the clinimetric properties of these scales in PD. A systematic review was conducted to identify anxiety scales that have either been validated or used in patients with PD. Six anxiety rating scales were identified. These were the Beck anxiety inventory, the hospital anxiety and depression scale, the Zung self-rating anxiety scale and anxiety status inventory, the Spielberger state trait anxiety inventory, and the Hamilton anxiety rating scale. In addition, Item 5 (anxiety) of the neuropsychiatric inventory was included in the review. No scales met the criteria to be "recommended," and all scales were classified as "suggested." Essential clinimetric information is missing for all scales. Because several scales exist and have been used in PD, the task force recommends further studies of these instruments. If these studies show that the clinimetric properties of existing scales are inadequate, development of a new scale to assess anxiety in PD should be considered.

Clinical diagnostic criteria for dementia associated with Parkinson's disease.

Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.

Levodopa in the treatment of Parkinson's disease: current controversies.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.