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Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.
To describe the current state of academic emergency medicine (EM) funding in Canada and develop recommendations to grow and establish sustainable funding.
A panel of eight leaders from different EM academic units was assembled. Using mixed methods (including a literature review, sharing of professional experiences, a survey of current EM academic heads, and data previously collected from an environmental scan), 10 recommendations were drafted and presented at an academic symposium. Attendee feedback was incorporated, and the second set of draft recommendations was further distributed to the Canadian Association Emergency Physicians (CAEP) Academic Section for additional comments before being finalized.
Recommendations were developed around the funding challenges identified and solutions developed by academic EM university-based units across Canada. A strategic plan was seen as integral to achieving strong funding of an EM unit, especially when it aligned with departmental and institutional priorities. A business plan, although occasionally overlooked, was deemed an important component for planning and sustaining the academic mission. A number of recommendations surrounding philanthropy consisted of creating partnerships with existing foundations and engaging multiple stakeholders and communities. Synergy between academic and clinical EM departments was also viewed as an opportunity to ensure integration of common missions. Education and networking for current and future leaders were also viewed as invaluable to ensure that opportunities are optimized through strong leadership development and shared experiences to further the EM academic missions across the country.
These recommendations were designed to improve the financial circumstances for many Canadian EM units. There is a considerable wealth of resources that can contribute to financial stability for an academic unit, and an annual networking meeting and continuing education on these issues will facilitate more rapid implementation of these recommendations.
Genetic testing in psychiatry promises to improve patient care through
advances in personalised medicine. However, there are few clinically
To determine whether patients with a well-established genetic subtype of
schizophrenia show a different response profile to the antipsychotic
clozapine than those with idiopathic schizophrenia.
We retrospectively studied the long-term safety and efficacy of clozapine
in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS
group) and half matched for age and clinical severity but molecularly
confirmed to have no pathogenic copy number variant (idiopathic
Both groups showed similar clinical improvement and significant
reductions in hospitalisations, achieved at a lower median dose for those
in the 22q11.2DS group. Most common side-effects were similarly prevalent
between the two groups, however, half of the 22q11.2DS group experienced
at least one rare serious adverse event compared with none of the
idiopathic group. Many were successfully retried on clozapine.
Individuals with 22q11.2DS-schizophrenia respond as well to clozapine
treatment as those with other forms of schizophrenia, but may represent a
disproportionate number of those with serious adverse events, primarily
seizures. Lower doses and prophylactic (for example anticonvulsant)
management strategies can help ameliorate side-effect risks. This first
systematic evaluation of antipsychotic response in a genetic subtype of
schizophrenia provides a proof-of-principle for personalised medicine and
supports the utility of clinical genetic testing in schizophrenia.
To study different radiological signs and sequences including apparent diffusion coefficient (ADC) and gradient echo (GRE) to differentiate degenerative parkinsonian syndromes.
Multiple system atrophy (MSA), Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CbD) differ in the pattern of neurodegeneration and cellular damage. Measuring the ADC, GRE sequences for paramagnetic substances and simple anatomical assessments have been reported individually to assist in separating some of these disorders, but have not been compared.
brain MRIs from May 2002 to February 2008 were retrospectively evaluated by raters blinded to the clinical diagnosis for predefined MRI signs on T1, T2 and GRE sequences. ADC values were quantitatively measured. Medical records were objectively analyzed using standard clinical criteria for different parkinsonian syndromes.
195 cases comprising of 61 PD, 15 MSA-P, 7 MSA-C, 21 PSP, 6 Corticobasal syndrome, 21 not fitting criteria and 64 controls were evaluated. 73% of patients with MSA-P had hypointensity of the putamen (compared to the pallidum) on GRE. The specificity of this sign to diagnose MSA-P was 90% versus PD and 76% versus PSP. When GRE hypointensity was combined with atrophy of the putamen the specificity improved to 98% (versus PD) and 95% (versus PSP) without altering the sensitivity. The ADC values were significantly higher in the middle cerebellar peduncle in cases with MSA-C versus controls, PD and PSP (p<0.001).
The combination of hypointensity and atrophy of the putamen on GRE is useful in differentiating MSA-P from other parkinsonian syndromes.