59 research outputs found
Population-based genotype-phenotype correlation to stratify incident cases of motor neurone disease in Scotland from 2015-2017
Background: Motor neurone disease (MND) refers to a spectrum of rapidly progressive
neurodegenerative diseases for which there remains no cure. A recognised and crucial
barrier to more accurate diagnosis, prognosis and treatment relates to phenotypic
heterogeneity. Recent discoveries in the genetic landscape of MND have resulted in an
accelerated research investment exploring aetiology of disease and basis of phenotypic
variation. Scotland benefits from a culture of longstanding MND data capture and an
integrated healthcare system.
Methods: I helped to develop Clinical Audit Research and Evaluation of MND (CARE-MND),
an evolution of the established Scottish MND Register. CARE-MND is a national electronic
platform for prospective, longitudinal monitoring of MND in Scotland. All people with MND
(pwMND) diagnosed in Scotland in 2015-17 were included in an epidemiological study of
incidence and prevalence of the disease. Patients who consented to sharing their medical
records via the Scottish MND Register were included for phenotypic characterisation and
prognostic modelling. Patients also donated DNA samples for genetic research to the
Scottish Regenerative Neurology Tissue Bank. Two cohorts were genotyped: i) a pilot cohort
of patients diagnosed 1989-2014 who were studied using a limited six-gene panel and ii) an
incident cohort of patients diagnosed 2015-17 who were genotyped using an extended 49
gene panel. Genotype-phenotype correlations were explored and the impact of genetics
included in prognostic models.
Results: By the end of my study period, the CARE-MND electronic platform was fully
integrated into routine clinical care across all 14 health boards in NHS Scotland. Using
capture-recapture statistics, coverage of the CARE-MND platform was 99% making it a
reliable resource for further study. Direct age-standardised incidence in 2015 was
3.42/100,000 (95% CI 2.99â3.91); in 2016, it was 2.89/100,000 (95% CI 2.50â3.34). This
represents a rise in incidence in Scotland by 36.0% over a 25-year period. The standardised
incidence was also 66.9% higher than Northern European estimates. Of 619 pwMND
diagnosed 2015-17, 437 (70.6%) consented to shared their phenotypic data. The following
variables significantly predicted mortality: rapid decline in the ALS Functional Rating Scale
Preslope, older age of onset, family history of MND and exposure to heavy metals/pesticides.
Atypical MND phenotypes (PLS, PBP and PMA), a long time to diagnosis and having ever
smoked predicted survival. Genetic epidemiology of a historical cohort (diagnosed 1989
2014) using a 6-gene panel revealed pathogenic or loss-of-function variants in 17%. Using an
extended panel, up to 22% had pathogenic variants or variants of uncertain significance with
pathogenic potential (VUS-P). The cohort was enriched for the Scottish p.I114T SOD1
founder mutation. Gene carrier status was associated with a family history of MND and other
neurological conditions (including Parkinsonâs disease and multiple sclerosis). Having a
C9orf72 repeat expansion was associated with an increased risk of cognitive impairment.
Having a genetic mutation of any kind did not influence overall survival.
Conclusions: Through CARE-MND, stratification of the MND population has facilitated
participation in observational studies and has established a platform for recruitment into
drug trials. The epidemiological data show a changing landscape of MND in Scotland with a
marked increase in incidence over 25 years. This is likely attributable to ascertainment in the
context of improved neurological services in Scotland. Early disability, older age and a family
history of MND are poor prognostic markers in the Scottish population, whereas a delay in
time from onset to diagnosis, atypical subtypes of MND and a history of smoking are
associated with longer survival. Clinical trial design in Scotland needs to reflect and control
for these factors. Using an extended 49-gene panel, 22% of patients have a potentially
pathogenic MND-associated variant. Diagnostic genotyping should be considered to inform
patientsâ prognosis and guide management
Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis
The authors would like to thank (i) the MRC Edinburgh Brain Bank for supplying all post-mortem brain material and the Scottish MND Register/CARE-MND Consortium for all clinical and demographic data. (ii) The Scottish MND Clinical Specialist, team in discussing and obtaining consent from MND patients for inclusion in these resources. (iii) People living with ALS and their families for making this research possible.Peer reviewe
Evaluation of cumulative cognitive deficits from electroconvulsive therapy
Background Electroconvulsive therapy (ECT) is the most effective acute treatment for severe depression, but widely held concerns about memory problems may limit its use. Aims To find out whether repeated or maintenance courses of ECT cause cumulative cognitive deterioration. Method Analysis of the results of 10 years of cognitive performance data collection from patients who have received ECT. The 199 patients had a total of 498 assessments, undertaken after a mean of 15.3 ECT sessions (range 0â186). A linear mixed-effect regression model was used, testing whether an increasing number of ECT sessions leads to deterioration in performance. Results The total number of previous ECT sessions had no effect on cognitive performance. The major factors affecting performance were age, followed by the severity of depression at the time of testing and the number of days since the last ECT session. Conclusions Repeated courses of ECT do not lead to cumulative cognitive deficits. This message is reassuring for patients, carers and prescribers who are concerned about memory problems and confusion during ECT. Electroconvulsive therapy (ECT) is the most effective acute treatment for severe depression,1 with reported remission rates above 50%.2,3 Although some reports demonstrate even higher remission rates (such as 75% in patients with psychotic depression4), these could be below 50% for treatment-resistant depression or in community settings.5,6 ECT is often portrayed in mainstream media as a barbaric treatment7 and its cognitive side-effects as profound and debilitating, leading to public, patient and carer concerns. ECT does cause retrograde amnesia and acute disorientation immediately following a treatment,8 however, research has suggested that this is only a short-lived side-effect. A meta-analysis by Semkovska & McLoughlin9 analysed the cognitive tests of 2981 patients from 84 studies, performed before and after single courses of ECT, and found that a decline in cognitive performance was limited to the first 3 days following a treatment. Patients showed no cognitive deterioration when tested 2 or more weeks after their last ECT session. This does not apply to retrograde amnesia, which was not part of this analysis, and it cannot be extended to cognitive functions that were not tested. Much less is known about the side-effects of long-term ECT, including maintenance ECT. A major concern of patients and some health professionals is that it could lead to progressive cognitive deficits, especially if given for prolonged periods of time. Small studies and case reports have addressed this question and have found no evidence to support this concern (see Discussion). Over the past 10 years we performed prospective cognitive tests on 199 patients, of whom 96 had >12 ECTsessions during their lifetime (the usual maximum duration of a single ECT course). We wanted to find out whether there was evidence that their cognitive performance deteriorated with the increasing number of ECT sessions
Corticostriatal functional connectivity of bothersome tinnitus in single-sided deafness
Subjective tinnitus is an auditory phantom perceptual disorder without an objective biomarker. Bothersome tinnitus in single-sided deafness (SSD) is particularly challenging to treat because the deaf ear can no longer be stimulated by acoustic means. We contrasted an SSD cohort with bothersome tinnitus (TIN; N = 15) against an SSD cohort with no or non-bothersome tinnitus (NO TIN; N = 15) using resting-state functional magnetic resonance imaging (fMRI). All study participants had normal hearing in one ear and severe or profound hearing loss in the other. We evaluated corticostriatal functional connectivity differences by placing seeds in the caudate nucleus and Heschlâs Gyrus (HG) of both hemispheres. The TIN cohort showed increased functional connectivity between the left caudate and left HG, and left and right HG and the left caudate. Within the TIN cohort, functional connectivity between the right caudate and cuneus was correlated with the Tinnitus Functional Index (TFI) relaxation subscale. And, functional connectivity between the right caudate and superior lateral occipital cortex, and the right caudate and anterior supramarginal gyrus were correlated with the TFI control subscale. These findings support a striatal gating model of tinnitus and suggest tinnitus biomarkers to monitor treatment response and to target specific brain areas for innovative neuromodulation therapies
Genotype-phenotype characterisation of long survivors with motor neuron disease in Scotland
Background:
We investigated the phenotypes and genotypes of a cohort of âlong-survivingâ individuals with motor neuron disease (MND) to identify potential targets for prognostication.
Methods:
Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined asâ>â8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls.
Results:
58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4, hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions.
Conclusions:
Long survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication
Functional and Structural Brain Plasticity in Adult Onset Single-Sided Deafness
Single-sided deafness (SSD) or profound unilateral hearing loss obligates the only serviceable ear to capture all acoustic information. This loss of binaural function taxes cognitive resources for accurate listening performance, especially under adverse environments or challenging tasks. We hypothesized that adults with SSD would manifest both functional and structural brain plasticity compared to controls with normal binaural hearing. We evaluated functional alterations using magnetoencephalographic imaging (MEGI) of brain activation during performance of a moderately difficult auditory syllable sequence reproduction task and assessed structural integrity using diffusion tensor imaging (DTI). MEGI showed the SSD cohort to have increased induced oscillations in the theta band over the left superior temporal cortex and decreased induced gamma band oscillations over the frontal and parietal cortices between 175 and 475 ms following stimulus onset. DTI showed the SSD cohort to have extensive fractional anisotropy (FA) reduction in both auditory and non-auditory tracts and regions. Overlaying functional and structural changes revealed by the two imaging techniques demonstrated close registration of cortical areas and white matter tracts that expressed brain plasticity. Hence, complete loss of input from one ear in adulthood triggers both functional and structural alterations to dorsal temporal and frontal-parietal areas
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