The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in... more The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab ...
The American journal of tropical medicine and hygiene, 2014
Studies examining the prevalence of zoonotic agents in the Caribbean are very limited. The object... more Studies examining the prevalence of zoonotic agents in the Caribbean are very limited. The objective of this study was to examine the seroprevalence of seven zoonotic agents among individuals residing on 10 English-speaking Caribbean countries. Sera from healthy, pregnant women were collected from Antigua-Barbuda, Belize, Bermuda, Dominica, Grenada, Jamaica, Montserrat, St. Kitts-Nevis, St. Lucia, and St. Vincent-Grenadines and tested for the presence of IgG antibodies to dengue virus, hepatitis E virus, hantaviruses, leptospiral agents, spotted fever group rickettsiae (SFGR), typhus group rickettsiae (TGR), and Coxiella burnetii (Q fever). The highest seroprevalence values were observed for dengue virus, SFGR, and leptospirosis, although the lowest seroprevalence values were observed for hepatitis E virus, C. burnetii, and TGR. Antibodies to hantaviruses were not detected in any individuals.
There is no consensus on the association between exposure to hydrocarbons and the risk of Parkins... more There is no consensus on the association between exposure to hydrocarbons and the risk of Parkinson's disease (PD). We conducted a systematic review and meta-analysis to summarise the epidemiological evidence and included a new large case-control study. Data were extracted following a predefined protocol. Risk estimates regarding the association between hydrocarbon exposure and PD were consolidated to produce a summary odds ratio (OR), 95% confidence intervals (CI), and p-value. In our case-control study, 1463 PD patients and 685 controls were recruited from clinical trials and completed a structured questionnaire describing their previous working exposure to hydrocarbons and other demographic measures. The association between exposure to hydrocarbons and risk of PD was evaluated using logistic regression. The systematic search identified 13 case-control studies matching the inclusion criteria. The meta-analysis included 3020 PD cases and 6494 controls. The summary OR was 1.32 (...
Exome sequencing is an effective strategy for identifying human disease genes. However, this meth... more Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analy...
With the exception of ApoE4, genome-wide association studies have failed to identify strong genet... more With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer's disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer's disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer's disease and…
Following the collapse of the Cuban economy in the early 1990s, epidemiologists in the Cuban Mini... more Following the collapse of the Cuban economy in the early 1990s, epidemiologists in the Cuban Ministry of Health noticed dramatic increases in reported outbreaks of ciguatera fish poisoning (CFP) in some coastal communities. This article summarizes the results of a ...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss o... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss of motor neurons. The cause of disease is unknown other than in the rare cases of familial disease arising from mutations in the superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed - including oxidative stress, excitotoxicity, mitochondrial dysfunction and abnormal protein aggregation - based on studies of human post mortem tissue, research on animal models, and in vitro work. Here we review the evidence for the main pathogenic mechanisms and outline how they might interact to cause motor neuron death. Clinical trials have as yet failed to identify any truly effective therapies in ALS, with only riluzole providing a modest improvement in survival. Ongoing trials are exploring the value of antiglutamatergic agents, including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective therapy will involve combinations of agents acting on different mechanisms. Gene therapy with neurotrophic factors will soon be in clinical trials, while work on stem cell therapy remains preclinical. In addition to finding effective therapies, research also needs to identify early disease markers because therapy is likely to be of most benefit when given early in the course of disease.
Protein degradation by the ubiquitin-proteasome pathway plays an important role in a variety of f... more Protein degradation by the ubiquitin-proteasome pathway plays an important role in a variety of fundamental cellular processes, including cell cycle regulation, transcription, antigen processing and muscle remodelling. Research into disorders associated with the ...
MAPT has been repeatedly linked with Parkinson&am... more MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.
BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in... more BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals ...
The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in... more The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab ...
The American journal of tropical medicine and hygiene, 2014
Studies examining the prevalence of zoonotic agents in the Caribbean are very limited. The object... more Studies examining the prevalence of zoonotic agents in the Caribbean are very limited. The objective of this study was to examine the seroprevalence of seven zoonotic agents among individuals residing on 10 English-speaking Caribbean countries. Sera from healthy, pregnant women were collected from Antigua-Barbuda, Belize, Bermuda, Dominica, Grenada, Jamaica, Montserrat, St. Kitts-Nevis, St. Lucia, and St. Vincent-Grenadines and tested for the presence of IgG antibodies to dengue virus, hepatitis E virus, hantaviruses, leptospiral agents, spotted fever group rickettsiae (SFGR), typhus group rickettsiae (TGR), and Coxiella burnetii (Q fever). The highest seroprevalence values were observed for dengue virus, SFGR, and leptospirosis, although the lowest seroprevalence values were observed for hepatitis E virus, C. burnetii, and TGR. Antibodies to hantaviruses were not detected in any individuals.
There is no consensus on the association between exposure to hydrocarbons and the risk of Parkins... more There is no consensus on the association between exposure to hydrocarbons and the risk of Parkinson's disease (PD). We conducted a systematic review and meta-analysis to summarise the epidemiological evidence and included a new large case-control study. Data were extracted following a predefined protocol. Risk estimates regarding the association between hydrocarbon exposure and PD were consolidated to produce a summary odds ratio (OR), 95% confidence intervals (CI), and p-value. In our case-control study, 1463 PD patients and 685 controls were recruited from clinical trials and completed a structured questionnaire describing their previous working exposure to hydrocarbons and other demographic measures. The association between exposure to hydrocarbons and risk of PD was evaluated using logistic regression. The systematic search identified 13 case-control studies matching the inclusion criteria. The meta-analysis included 3020 PD cases and 6494 controls. The summary OR was 1.32 (...
Exome sequencing is an effective strategy for identifying human disease genes. However, this meth... more Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analy...
With the exception of ApoE4, genome-wide association studies have failed to identify strong genet... more With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer's disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer's disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer's disease and…
Following the collapse of the Cuban economy in the early 1990s, epidemiologists in the Cuban Mini... more Following the collapse of the Cuban economy in the early 1990s, epidemiologists in the Cuban Ministry of Health noticed dramatic increases in reported outbreaks of ciguatera fish poisoning (CFP) in some coastal communities. This article summarizes the results of a ...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss o... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss of motor neurons. The cause of disease is unknown other than in the rare cases of familial disease arising from mutations in the superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed - including oxidative stress, excitotoxicity, mitochondrial dysfunction and abnormal protein aggregation - based on studies of human post mortem tissue, research on animal models, and in vitro work. Here we review the evidence for the main pathogenic mechanisms and outline how they might interact to cause motor neuron death. Clinical trials have as yet failed to identify any truly effective therapies in ALS, with only riluzole providing a modest improvement in survival. Ongoing trials are exploring the value of antiglutamatergic agents, including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective therapy will involve combinations of agents acting on different mechanisms. Gene therapy with neurotrophic factors will soon be in clinical trials, while work on stem cell therapy remains preclinical. In addition to finding effective therapies, research also needs to identify early disease markers because therapy is likely to be of most benefit when given early in the course of disease.
Protein degradation by the ubiquitin-proteasome pathway plays an important role in a variety of f... more Protein degradation by the ubiquitin-proteasome pathway plays an important role in a variety of fundamental cellular processes, including cell cycle regulation, transcription, antigen processing and muscle remodelling. Research into disorders associated with the ...
MAPT has been repeatedly linked with Parkinson&am... more MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.
BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in... more BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals ...
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Papers by Karen Morrison