Quantifying disease progression in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic. Ann Neurol 2014;76:643–657     

Mapping Canadian Data Assets to Generate Real-World Evidence: Lessons Learned from Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration’s RWE Data Working Group

Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8–11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration’s Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.     

Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies

Hedonistic homeostatic dysregulation is a neuropsychological behavioural disorder associated with substance misuse and addiction. The disorder has been recognised as a consequence of dopamine replacement therapy (DRT) in 15 patients with Parkinson's disease. The syndrome typically develops in male patients with early onset Parkinson's disease, and can occur with orally and subcutaneously administered DRT. These patients take increasing quantities of their DRT, despite increasingly severe drug induced dyskinesias, and may develop a cyclical mood disorder with hypomania or manic psychosis. There is impairment of social and occupational functioning. Tolerance develops to mood elevating effects of DRT and a negative affective withdrawal state occurs if the drugs are withdrawn or doses decreased. The clinical features and guidelines for managing this syndrome are discussed. A set of diagnostic criteria for further investigating this condition is proposed.     

Cellular localization of somatostatin mRNA in rat retina

In an attempt to determine the localization of the messenger RNA (mRNA) encoding somatostatin in the rat retina, we studied Sprague-Dawley rats by in situ hybridization histochemistry using radiolabelled oligodeoxyribonucleotides complementary for rat somatostatin mRNA. Among the layers of retina, we found specific labelling in the soma of some cells in the innermost and outermost laminae of the inner nuclear layer and in the ganglion cell layer; no specific labelling was observed in the inner and outer plexiform layers or in the outer nuclear layer. These data indicate the major site of somatostain synthesis within the rat retina.     

An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule, a proteomics approach

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neurofibrillary tangles, senile plaques, and loss of synapses. Many studies support the notion that oxidative stress plays an important role in AD pathogenesis. Previous studies from our laboratory employed redox proteomics to identify oxidatively modified proteins in the AD inferior parietal lobule (IPL) and hippocampus. The proteins were consistent with biochemical or pathological alterations in AD and have been central to further investigations of the disease. The present study focused on the identification of specific targets of protein S-glutathionylation in AD and control IPL by using a redox proteomics approach. For AD IPL, we identified deoxyhemoglobin, alpha-crystallin B, glyceraldehyde phosphate dehydrogenase (GAPDH), and alpha-enolase as significantly S-glutathionylated relative to these brain proteins in control IPL. GAPDH and alpha-enolase were also shown to have reduced activity in the AD IPL. This study demonstrates that specific proteins are sensitive to S-glutathionylation, which most likely is due to their sensitivity to cysteine oxidation initiated by the increase in oxidative stress in the AD brain.     

Intracerebroventricular kainic acid administration in adult rat alters hippocampal calbindin and non-phosphorylated neurofilament expression

Calbindin and non-phosphorylated neurofilament proteins were assessed in hippocampus following a unilateral intracerebroventricular kainic acid injection at 4, 26, and 60 days post-lesion, using immunocytochemical expression. The density of calbindin-positive non- pyramidal neurons throughout the hippocarnpus showed no significant alteration at 4 days post-lesion, a significant decrease at 26 days post-lesion, and a partial recovery at 60 days post-lesion. In addition, calbindin immunoreactivity was dramatically reduced at 26 days post-lesion in the CA1 pyramidal and dentate granule cell layers and the mossy fibers, bilaterally. Although not significant statistically, most of these reductions showed signs of reversal at 60 days post-lesion except the CA1 pyramidal cell layer where the dramatic reductions persisted. Neurofilaments were also altered throughout the post-lesion period, particularly in abnormal expression of non-phosphorylated neurofilament proteins in mossy fibers. The apparent return of calbindin immunoreactivity in non-pyramidal neurons by 60 days post-lesion suggests that recovery from the lesion may involve remaining neuronal elements which either become reactivated with time or have the capability to express normal levels of calbindin with re-innervation. On the other hand, prolonged calbindin reductions in superficial CA1 pyramidal cells suggest sustained down-regulation of calbindin expression owing to persistent reductions in the activity of these neurons. The temporal correlation of the expression of non-phosphorylated neurofilamenta in mossy fibers with their sprouting response following target loss suggests a potential role for non-phosphorylated neurofilaments in neuronal plasticity involving axonal sprouting. Alternatively, it may also suggest that injury- induced neurofilament modifications are either conducive or permissive for axonal sprouting. © 1995 Wiley-Liss, Inc.     

The effect of parathyroidectomy on bone mineral density in primary hyperparathyroidism.

Bone mineral density was studied before, and at one year after successful parathyroidectomy in six postmenopausal, three premenopausal females and one male with primary hyperparathyroidism. Dual photon absorptiometry was used to measure bone mineral density at the lumbar spine in all subjects, and at three areas of the hip in eight of the subjects. There was no significant change in bone mineral density at the lumbar spine after one year. Bone mineral density increased 7.4% at the femoral neck from 0.822 (SEM 0.053) g/cm2 to 0.895 (0.04) g/cm2; p less than 0.01, 8.7% at Wards triangle from 0.681 (0.065) g/cm2 to 0.745 (0.07) g/cm2; p less than 0.02. A 5.6% increase at the trochanteric region from 0.785 (0.053) g/cm2 to 0.803 (0.053) g/cm2 was not significant. These results indicate that significant increases occur in bone mineral density at the hip, but not at the lumbar spine at one year after parathyroidectomy in patients with primary hyperparathyroidism.     

Comprehensive linkage and linkage heterogeneity analysis of 4344 sibling pairs affected with hypertension from the Family Blood Pressure Program

Linkage analyses of complex, multifactorial traits and diseases, such as essential hypertension, have been difficult to interpret and reconcile. Many published studies provide evidence suggesting that different genes and genomic regions influence hypertension, but knowing which of these studies reflect true positive results is challenging. The reasons for this include the diversity of analytical methods used across these studies, the different samples and sample sizes in each study, and the complicated biological underpinnings of hypertension. We have undertaken a comprehensive linkage analysis of 371 autosomal microsatellite markers genotyped on 4,334 sibling pairs affected with hypertension from five ethnic groups sampled from 13 different field centers associated with the Family Blood Pressure Program (FBPP). We used a single analytical technique known to be robust to interpretive problems associated with a lack of completely informative markers to assess evidence for linkage to hypertension both within and across the ethnic groups and field centers. We find evidence for linkage to a number of genomic regions, with the most compelling evidence from analyses that combine data across field center and ethnic groups (e.g., chromosomes 2 and 9). We also pursued linkage analyses that accommodate locus heterogeneity, which is known to plague the identification of disease susceptibility loci in linkage studies of complex diseases. We find evidence for linkage heterogeneity on chromosomes 2 and 17. Ultimately our results suggest that evidence for linkage heterogeneity can only be detected with large sample sizes, such as the FBPP, which is consistent with theoretical sample size calculations.