Mapping preclinical compensation in Parkinson's disease: An imaging genomics approach

Mutations in the Parkin (PARK2) and PINK1 gene (PARK 6) can cause recessively inherited Parkinson's disease (PD). The presence of a single Parkin or PINK1 mutation is associated with a dopaminergic nigrostriatal dysfunction and conveys an increased risk to develop PD throughout lifetime. Therefore neuroimaging of non‐manifesting individuals with a mutant Parkin or PINK1 allele opens up a window for the investigation of preclinical and very early phases of PD in vivo. Here we review how functional magnetic resonance imaging (fMRI) can be used to identify compensatory mechanisms that help to prevent development of overt disease. In two separate experiments, Parkin mutation carriers displayed stronger activation of rostral supplementary motor area (SMA) and right dorsal premotor cortex (PMd) during a simple motor sequence task and anterior cingulate motor area and left rostral PMd during internal movement selection as opposed to externally cued movements. The additional recruitment of the rostral SMA and right rostral PMd during the finger sequence task was also observed in a separate group of nonmanifesting mutation carriers with a single heterozygous PINK1 mutation. Because mutation carriers were not impaired at performing the task, the additional recruitment of motor cortical areas indicates a compensatory mechanism that effectively counteracts the nigrostriatal dysfunction. These first results warrant further studies that use these imaging genomics approach to tap into preclinical compensation of PD. Extensions of this line of research involve fMRI paradigms probing nonmotor brain functions. Additionally, the same fMRI paradigms should be applied to nonmanifesting mutation carriers in genes linked to autosomal dominant PD. This will help to determine how “generically” the human brain compensates for a preclinical dopaminergic dysfunction. © 2009 Movement Disorder Society     

Are radiographs needed when MR imaging is performed for non-acute knee symptoms in patients younger than 45 years of age?

Objective The objective was to determine the value of radiographs in young adults with non-acute knee symptoms who are scheduled for magnetic resonance imaging (MRI). Materials and methods Nine hundred and sixty-one consecutive patients aged between 16 and 45 years with knee symptoms of at least 4 weeks’ duration were prospectively included in three participating hospitals. After applying exclusion criteria, 798 patients remained. Exclusion criteria were previous knee surgery (including arthroscopy) or MRI, history of rheumatoid arthritis, clinical diagnosis of retropatellar chondromalacia, contra-indication for MRI and recent trauma. We identified two groups: group A with no history of trauma (n = 332), and group B with an old (>4 weeks) history of trauma (n = 466). Patients had a standardized history taken, and underwent a physical exam, antero-posterior (AP) and lateral radiographs and MRI. We evaluated the radiographs and MRI for osseous lesions, articular surface lesions, fractures, osteoarthritis, loose bodies, bone marrow edema and incidental findings. Subsequently, patients with osseous abnormalities (Kellgren grade 1 and 2 excluded) on radiographs and a matched control group was evaluated again using MRI without radiographs. Results Median duration of symptoms was 20 weeks. In group A, radiographs showed 36 osseous abnormalities in 332 patients (10.8%). Only 13 of these, all Kellgren grade 1 osteoarthritis, were not confirmed on MRI. MRI showed 72 (21.7%) additional abnormalities not confirmed on radiographs. In group B, radiographs showed 40 osseous abnormalities (8.6%) in 466 patients. Only 15 of these, all Kellgren grade 1 osteoarthritis, were not confirmed on MRI. MRI showed 194 (41.6%) additional abnormalities not confirmed on radiographs. The second evaluation of MRI without radiographs in 34 patients was identical to the first MRI evaluation. Common lesions were significantly more often diagnosed with MRI than with radiographs. Conclusion Radiographs should not be obtained routinely when MRI is being performed in young adults with non-acute knee complaints because the yield and added value to MRI are low.     

Bone marrow edema-like lesions change in volume in the majority of patients with osteoarthritis; associations with clinical features

It has been suggested that bone marrow edema-like (BME) lesions in the knee are associated with progression of osteoarthritis (OA). The purpose of our study in patients with OA was to evaluate prospectively changes of BME lesions over 2 years and their relationship with clinical features. Magnetic resonance (MR) images of the knee were obtained from 182 patients (20% male; aged 43–76 years; mean age 59 years) who had been diagnosed with familial symptomatic OA at multiple joint sites. MR images were made at baseline and at 2 years follow-up. BME lesions in 2 years were associated with clinical features assessed by Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores. A total of 327 BME lesions were recorded. Total size of BME lesions changed in 90 patients (66%). Size of individual lesions changed in 147 foci (45%): new lesions appeared in 69 (21%), existing lesions disappeared in 32 (10%), increased in size in 26 (8%) and decreased in size in 20 (6%) lesions. Increase or decrease of BME lesions, over a 2-year time period, was not associated with severity of WOMAC scores. BME lesions fluctuated in the majority of patients with OA over a 2-year time period. These changes were not associated with severity of WOMAC scores at the study end point.     

A weak balance: the contribution of muscle weakness to postural instability and falls

Muscle strength is a potentially important factor contributing to postural control. In this article, we consider the influence of muscle weakness on postural instability and falling. We searched the literature for research evaluating muscle weakness as a risk factor for falls in community-dwelling elderly individuals, for evidence that strength training reduces falls, and for pathophysiological evidence from patients with neuromuscular disease that supports the link between muscle weakness and falls. In virtually all studies that included strength testing, muscle weakness was a consistent risk factor for falls in the elderly. Studies that evaluated the merits of muscle strength training often showed a reduction in fall rates, particularly when strength training was a component of a multifactorial intervention, although it was unclear whether strength training alone led to a fall reduction. Surprisingly few studies addressed the pathophysiological relationship between muscle strength and balance control. We conclude that muscle weakness is an important risk factor for falls that is potentially amenable to therapeutic intervention, and that future studies should further clarify the role of muscle weakness in balance control and the pathophysiology of falls.     

Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants

Objectives: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants. Method: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 ± 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow‐up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow‐up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow‐up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.     

Decreased p38 MAPK activity in end-stage failing human myocardium: p38 MAPK alpha is the predominant isoform expressed in human heart.

Short duration exposure to cellular stresses have been shown to activate p38 mitogen-activated protein kinase (MAPK) in cultured rat ventricular cardiomyocytes and isolated perfused hearts; however, effects of chronic stress on p38 MAPK are not well understood. This study determined whether alterations in the p38 MAPK pathway occurred prior to end-stage human heart failure. The p38 MAPK alpha isoform was detectable in human cardiac tissue. However, carefully controlled analysis of protein and message in this study demonstrated an absence of the p38 MAPK beta -isoform. Low levels of message for the non-SB203580 sensitive p38 MAPK gamma and delta isoforms were also detected in both normal and failing human myocardium. Ischemic and idiopathic end-stage failing human hearts were compared to non-failing hearts for both p38 alpha MAPK protein level and total p38 MAPK activity. Western blotting techniques demonstrated no significant changes in total p38 alpha MAPK content. However, approximately 75% decreases in active/phosphorylated p38 MAPK (P<0.005) were observed in both ischemic and idiopathic failing hearts compared to non-failing hearts. In-gel kinase assays confirmed that activated p38 MAPK, detected by Western blotting, phosphorylated its potential downstream targets. When compared to non-failing hearts, approximately 46% decreases in p38 MAPK phosphorylation of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK-2) were observed in ischemic and idiopathic failing hearts (P=0.03 and P=0.04 respectively). Active p38 MAPK was localized to sarcomeric structures in the cytosol of myocytes by confocal immunofluorescence microscopy. The correlation between decreased MAPKAPK-2 phosphorylation and loss of active p38 MAPK in failing human myocytes suggests that decreases in the activation of p38 MAPK alpha, the predominant cardiac isoform, occur prior to end-stage heart failure.