Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations

<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (<it>PGRN</it>) gene.</p> <p>Results</p> <p>Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying <it>PGRN </it>mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of <it>PGRN </it>mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.</p> <p>Conclusions</p> <p>Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by <it>PGRN </it>mutations and provides new insight into potential future therapeutic options.</p

The genetics and neuropathology of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of disorders characterized by disturbances of behavior and personality and different types of language impairment with or without concomitant features of motor neuron disease or parkinsonism. FTLD is characterized by atrophy of the frontal and anterior temporal brain lobes. Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions. Rather than the type of proteinopathy, the site of neurodegeneration correlates relatively well with the clinical presentation of FTLD. Molecular genetic studies identified five disease genes, of which the gene encoding the tau protein (MAPT), the growth factor precursor gene granulin (GRN), and C9orf72 with unknown function are most frequently mutated. Rare mutations were also identified in the genes encoding valosin-containing protein (VCP) and charged multivesicular body protein 2B (CHMP2B). These genes are good markers to distinguish underlying neuropathological phenotypes. Due to the complex landscape of FTLD diseases, combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis. Although major progress has been made in FTLD research in recent years, further studies are needed to completely map out and correlate the clinical, pathological and genetic entities, and to understand the underlying disease mechanisms. In this review, we summarize the current state of the rapidly progressing field of genetic, neuropathological and clinical research of this intriguing condition

Seasonality, risk factors and burden of community-acquired pneumonia in COPD patients: a population database study using linked health care records

Nicholas P Williams,1,2 Ngaire A Coombs,3 Matthew J Johnson,4 Lynn K Josephs,3,4 Lucy A Rigge,2,4 Karl J Staples,2 Mike Thomas,1,3,4 Tom MA Wilkinson1,2,4 1Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, 2Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, 3Primary Care and Population Sciences, Faculty of Medicine, Southampton General Hospital, 4NIHR CLAHRC Wessex, Faculty of Health Sciences, University of Southampton, Southampton General Hospital, Southampton, UK Background: Community-acquired pneumonia (CAP) is more common in patients with COPD than in the adult general population, with studies of hospitalized CAP patients consistently reporting COPD as a frequent comorbidity. However, despite an increasing recognition of its importance, large studies evaluating the incidence patterns over time, risk factors and burden of CAP in COPD are currently lacking.Methods: A retrospective observational study using a large UK-based database of linked primary and secondary care records was conducted. Patients with a diagnosis of COPD aged &ge;40&nbsp;years were followed up for 5&nbsp;years from January 1, 2010. CAP and exacerbation episodes were identified from hospital discharge data and primary care coding records, and rates were calculated per month, adjusting for mortality, and displayed over time. In addition, baseline factors predicting future risk of CAP and hospital admission with CAP were identified.Results: A total of 14,513 COPD patients were identified: 13.4% (n=1,938) had &ge;1 CAP episode, of whom 18.8% suffered from recurrent (&ge;2) CAP. Highest rates of both CAP and exacerbations were seen in winter. A greater proportion of frequent, compared to infrequent, exacerbators experienced recurrent CAP (5.1% versus 2.0%, respectively, P&lt;0.001); 75.6% of CAP episodes were associated with hospital admission compared to 22.1% of exacerbations. Older age and increasing grade of airflow limitation were independently associated with increased odds of CAP and hospital admission with CAP. Other independent predictors of future CAP included lower body mass index, inhaled corticosteroid use, prior frequent exacerbations and comorbidities, including ischemic heart disease and diabetes.Conclusion: CAP in COPD demonstrates clear seasonal patterns, with patient characteristics predictive of the odds of future CAP and hospital admission with CAP. Highlighting this burden of COPD-associated CAP during the winter period informs us of the likely triggers and the need for more effective preventive strategies. Keywords: COPD exacerbations, exacerbation frequency, community-acquired pneumonia, comorbidity&nbsp