166 research outputs found
The immediate impact of the COVID-19 pandemic on motor neuron disease services and mortality in Scotland
Get PDFThe article The immediate impact of the COVID‑19 pandemic on motor neuron disease services and mortality in Scotland, written by Stella A. Glasmacher, Juan Larraz, Arpan R. Mehta, Patrick K. A. Kearns, Michael Wong, Judith Newton, Richard Davenport, George Gorrie, Ian Morrison, Javier Carod Artal, Siddharthan Chandran, Suvankar Pal and CARE-MND Consortium, was originally published online on 5 September 2020 with Open Access under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.</p
Investigating the clinical correlation between sporadic Creutzfeldt Jakob disease and presence of other neurodegenerative pathologies
Get PDFINTRODUCTION:
Sporadic Creutzfeldt Jakob Disease (sCJD) is a rapidly progressive and fatal neurodegenerative disorder. Age-specific mortality rates for sCJD have increased up to 65-79 years over the past four decades. Of interest is an apparent reduced incidence at 80 and over. It has been hypothesised that the apparent decline in incidence of sCJD in older adults could be due to the inhibitory effects of the Alzheimer’s disease (AD) associated amyloid β-protein(Aβ) on prion propagation.
METHODS:
Retrospective case note review of cases of definite sCJD over a 3 year period from 2016-2018. Cases evaluated for the presence of additional neurodegenerative pathology on neuropathological examination of brain material. Specifically Aβ, tau, α-synuclein and cerebral amyloid angiopathy (CAA).
RESULTS:
123 cases of definite sCJD were identified in the UK between 2016-2018. 56/112 (50%) of cases show evidence of co-existing pathology in addition to sCJD. Cases with co-pathology had a higher age at death by 6.3 years (95% CI (2.95, 9.59 ) p<0.001). Median disease duration from onset of symptoms was shorter in the sCJD plus co-pathology group when compared to the sCJD only group by 1.3 months (p=0.205). Co-pathology cases were more likely to present with cognitive decline or neuropsychiatric features (p=0.025). Co-pathology cases were slightly more likely to test negative for CSF RT-QuIC and MRI. Patients with co-pathology were slightly less likely to be assessed by the National CJD Research and Surveillance Unit in life.
CONCLUSION:
This data suggests a potential association between the presence of other neurotoxic proteins in the brain of sCJD patients with older age of onset and distinct presenting symptoms. Findings have implications for clinical care and surveillance of sCJD in older adults
Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in the assessment of early onset dementia
Get PDFEarly onset dementia is the gradual cognitive decline that interferes with
independence in everyday activities, when it occurs in people younger than 65
years old (Fadil et al., 2009; American Psychiatric Association, 2013). The
Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was originally
developed to assess cognitive and behavioural changes observed in
amyotrophic lateral sclerosis (ALS) (Abrahams et al. 2014); as between 10-
15% of ALS patients develop frontotemporal dementia, and an additional 35%
develop a milder cognitive impairment of frontotemporal dysfunction
(Goldstein and Abrahams, 2013; Strong et al., 2017). The ECAS includes the
domains of language, fluency, and executive functions for the assessment of
ALS, but it also includes the domains of memory and visuospatial abilities to
differentiate changes from other pathologies, such as Alzheimer’s Disease
(AD) (Abrahams et al. 2014). In addition, the ECAS includes a behavioural
interview. In this thesis I explore whether the ECAS is a sensitive test to the
types of cognitive and behavioural changes in people with early onset
dementia without Amyotrophic Lateral Sclerosis (ALS).
In the first study my objectives were: to investigate the relationship between
the ECAS and the Addenbrooke’s Cognitive Examination (ACE-III); to
investigate the effects of age, education, and IQ on the ECAS, and create
appropriate cut-off scores to determine abnormality. I assessed 80 healthy
participants divided into four groups according to age and education. The
ECAS and the ACE-III had a significant correlation indicating good convergent
validity. IQ, followed by age, were the strongest predictors of the total ECAS
score. While IQ predicted 46% of the ACE-III variance, it only predicted 24%
of the ECAS variance. I created abnormality cut-off scores adjusted for age
and education. This research was published in De Icaza Valenzuela et al.
(2018).
In the second study my aim was to determine the sensitivity of the ECAS to
behavioural variant frontotemporal dementia (bvFTD) without ALS, AD,
primary progressive aphasia (PPA) without ALS, posterior cortical atrophy
(PCA) and mild cognitive impairment (MCI). I also validated the ECAS against
a comprehensive neuropsychological assessment, and compared it with the
ACE-III, for each diagnosis. We additionally performed a qualitative thematic
analysis of the ECAS behavioural interviews to determine the differences in
themes between the diagnoses of bvFTD and AD. The study included 16
people with bvFTD (without ALS), 32 with AD, 12 with MCI, 13 with PPA, 6
with PCA and 48 healthy controls. The ECAS was more sensitive than the
ACE-III to detect bvFTD, AD, MCI and PPA; with equal sensitivity to detect
PCA. The anterior functions (comprising executive, fluency and language
scores) composite score was sensitive to bvFTD; while the posterior
functions (comprising memory and visuospatial scores) composite score
was sensitive to AD. The ECAS was able to detect cognitive impairment as
determined by a comprehensive neuropsychological assessment in most of
the patients. A cut-off of 4 or more behavioural domains affected differentiated
well between bvFTD and AD, while different themes emerged between the
groups in the qualitative analysis of the behavioural interview.
Finally, for the third study my objectives were: to investigate the relationship
between the ECAS and functional severity of dementia; to validate the
behavioural interview of the ECAS with other behavioural screens used to
assess FTD; and to determine whether the ECAS scores changed over time
in bvFTD, AD, MCI, PPA, and PCA. For this purpose, I did a longitudinal study
and analysed the correlations between the ECAS with the Clinical Dementia
Rating Scale (CDR-FTLD), the Frontal Behavioural Inventory (FBI), and the
Frontotemporal Dementia Rating Scale (FRS). I assessed 56 patients on the
first assessment, 29 on the second assessment and 13 on the third
assessment. The ECAS total score had good convergent validity with the
CDR-FTLD severity classification, while the ECAS behavioural screen had
convergent validity with the FBI, FRS and CDR-FTLD. I created an impairment
cut-off score of 96 to differentiate the groups of questionable versus mild
dementia based on the CDR-FTLD. The CDR-FTLD, FIQ, FBI, and FRS
predicted 71.3% of the variance of the ECAS Total Score. The variance of the
ECAS behavioural score was predicted 74.7% by the FBI, FIQ and age. FRS
was the single variable to predict attrition by 20.4%. In our study there was no
significant difference of ECAS scores between assessments.
The ECAS proved to be a valid test to assess the cognitive and behavioural
impairments in people with early onset dementia without ALS. It was more
sensitive than the ACE-III at detecting dementia in most of the patient groups,
with the exception of the PCA group where they had equal sensitivity. The
ECAS had also equal sensitivity to detect bvFTD, PPA and PCA as an
extensive neuropsychological assessment. It could therefore be used as a first
assessment in early onset dementia clinics
Peripheral reaching in Alzheimer's disease and mild cognitive impairment
Get PDFRecent evidence has implicated areas within the posterior parietal cortex (PPC) as among the first to show pathophysiological changes in Alzheimer's disease (AD). Focal brain damage to the PPC can cause optic ataxia, a specific deficit in reaching to peripheral targets. The present study describes a novel investigation of peripheral reaching ability in AD and mild cognitive impairment (MCI), to assess whether this deficit is common among these patient groups. Individuals with a diagnosis of mild-to-moderate AD, or MCI, and healthy older adult controls were required to reach to targets presented in central vision or in peripheral vision using two reaching tasks; one in the lateral plane and another presented in radial depth. Pre-registered case–control comparisons identified 1/10 MCI and 3/17 AD patients with significant peripheral reaching deficits at the individual level, but group-level comparisons did not find significantly higher peripheral reaching error in either AD or MCI by comparison to controls. Exploratory analyses showed significantly increased reach duration in both AD and MCI groups relative to controls, accounted for by an extended Deceleration Time of the reach movement. These findings suggest that peripheral reaching deficits like those observed in optic ataxia are not a common feature of AD. However, we show that cognitive decline is associated with a generalised slowing of movement which may indicate a visuomotor deficit in reach planning or online guidance
Population-based genotype-phenotype correlation to stratify incident cases of motor neurone disease in Scotland from 2015-2017
Get PDFBACKGROUND:
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 2.99–3.91); in 2016, it was 2.89/100,000 (95% CI 2.50–3.34). 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 Parkinson’s 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
patients’ prognosis and guide management
Influence of age on case ascertainment in CJD
Get PDFAgeing is the greatest risk factor for most forms of dementia. Variant
Creutzfeldt-Jakob Disease (vCJD) however is predominantly a disease of
younger adults and sporadic CJD (sCJD), although a disease of the older
population, mainly affects those under 80 years of age. The very low age-specific
incidence of both vCJD and sCJD in the oldest age group may, in
part, be due to case under ascertainment, perhaps due to a lack of familiarity
with CJD, or atypical clinical presentation of CJD
In the UK, suspect cases of CJD are referred by clinicians to the National CJD
Research & Surveillance Unit (NCJDRSU) for clinical assessment and
epidemiological review. Case ascertainment in CJD is important not only for
appropriate clinical care but also, due to the potential for person-to-person
transmission of the CJD agent through medical procedures, to help protect
public health. In this thesis:
1) I describe the clinical and referral characteristics of CJD patients diagnosed
later in their disease progression and determine if these characteristics differ
in those diagnosed earlier. A retrospective review of CJD cases referred to
the NCJDRSU, for vCJD between 1995 and 2015 (n = 177) and for sCJD
between 2010 and 2015 (n = 584) was undertaken. Age was significantly
associated with timing of diagnosis, with later diagnoses occurring in older
patients, and differences in clinical and referral characteristics between these
and younger patients.
2) I also pilot a study of enhanced CJD surveillance in the older population.
Since January 2016, patients aged ≥65 years seen in NHS Lothian with a
diagnosis of non-CJD dementia but with atypical features (e.g. rapid speed of
progression or focal neurology) have been invited to participate in a study to
investigate whether atypical CJD might underlie the diagnosis of some
patients with dementia. For each participant, a clinical examination was
undertaken, with consent, including Addenbrooke’s Cognitive Examination–III,
the frontal assessment battery, the hospital anxiety and depression scale,
Barthel’s Index, and the Edinburgh Motor Assessment Scale. In addition, MRI
was undertaken (including DWI and FLAIR sequences), a blood sample was
taken for codon-129 subtyping and patients were consented for donation of
brain tissue in the event of their death. Ten patients were recruited during the
initial 6 months of study. Although patients had individual features of CJD
there was no evidence of CJD clinically. No patients however reached postmortem
during this initial study period. Barriers to referral, including clinician
time pressures, likely impacted study referral
Vision, attention and action in posterior cortical atrophy and other dementias
Get PDFPosterior Cortical Atrophy (PCA) is a rare, progressive dementia characterised
by visuospatial and visuoperceptual deficits (often with intact visual acuity),
and a generally younger age of onset than typical Alzheimer’s disease (AD)
(Aresi & Giovagnoli, 2009; Caixeta, Taleb, Ghini, Dias Soares, de Melo Caizera &
Vargas, 2013; Mendez, Ghjarania & Perryman, 2002). Patients with PCA
typically present with fewer memory deficits, better verbal fluency, and better
insight into their diagnosis compared with typical AD, although PCA and AD
tend to converge clinically at advanced stages of disease progression (Lehmann
et al., 2012). Despite being identified by Benson and colleagues three decades
ago, there are still no widely agreed clinical diagnostic criteria for PCA and it
remains relatively poorly understood (Benson, Davis & Snyder, 1988; Crutch et
al., 2017).
This PhD study was comprised of two phases. The initial screening phase
involved a diverse battery of assessments with two main aims. First, this battery
was intended to investigate the sensitivity and specificity of different screening
tests in discriminating PCA patients (n = 6) from patients with other
neurodegenerative dementias (n = 21) (typical Alzheimer’s disease,
frontotemporal dementia, Lewy body dementia, corticobasal degeneration, and
primary progressive aphasia). The Modified Luria Alternating Square and
Triangles (M-LAST) task achieved the highest sensitivity and specificity, closely
followed by target cancellation and bisection tasks. The M-LAST task has not
been reported previously in the assessment of PCA patients, but may have
considerable potential for use in diagnostic settings. Similarly, an unusual
variant of the bisection task (gap bisection, McIntosh et al., 2004) yielded the
most impressive sensitivity for PCA. The secondary aim of the screening phase
was to identify whether patients with other neurodegenerative diseases
demonstrated deficits on the assessments which were specific to early visual
function, as this is an area that has not been addressed previously in the
literature. There was evidence of significant impairment for patients other than
PCA on a number of measures. However, the most striking results from patients
with dementias other than PCA were obtained on the second phase of
assessment.
The second laboratory-based phase aimed to more fully characterise the
visuoattentional deficits associated with PCA (n = 5) and other dementias (n =
13), through the use of eye-tracking and motion-tracking technology. The PCA
patients proved difficult to test under these conditions, as their visual
impairments were so advanced and generalised that they appeared almost
functionally blind on some tests. The most exciting novel results were obtained
from patients with AD, in whom evidence of optic ataxia (misreaching to
peripheral targets) was found for three of the four AD patients tested on a
pointing task. These results, discussed in context with other recently published
evidence (Gordon et al., 2018), suggest that screening for optic ataxia may have
potential as a behavioural symptom potentially sensitive to early neuronal
changes associated with AD.
A systematic review of the literature was conducted in order to investigate the
use of visual attention or visuomotor-specific assessments in the evaluation of
patients with PCA. A case study was conducted of visual form agnosic patient
DF, in whom recent evidence of optic ataxia has been found (Rossit et al., 2018;
Hesse, Ball & Schenk, 2012, 2014). Strong evidence of optic ataxic-like pointing
errors was observed in patient DF, with preserved grip scaling, implicit
avoidance of obstacles and perceptual matching. An additional study on healthy
participants was conducted in order to test whether attentional demands
modulate performance on a visuomotor pointing task. The results indicated that
increasing attentional demands led to optic ataxic-like pointing errors, thus the
experimental manipulation appeared to serve as a model of optic ataxia in the
healthy brain
Validation of Revised International Creutzfeldt-Jakob Disease Surveillance Network Diagnostic Criteria for Sporadic Creutzfeldt-Jakob Disease
No full textValidation of the 2017 International Creutzfeldt-Jakob Disease Surveillance Network diagnostic criteria for sporadic Creutzfeldt-Jakob disease
Get PDFSporadic Creutzfeldt-Jakob disease (sCJD) is the commonest human prion disease. sCJD is rapidly-progressive, universally fatal and transmissible. Rapid, accurate in-life diagnosis is imperative for epidemiological surveillance and public health activities, to exclude treatable differentials and facilitate supportive care. In 2017 the International CJD Support Network diagnostic criteria were revised to incorporate i) cortical ribboning on magnetic resonance imaging (MRI) and ii) the real-time quaking-induced conversion (RT-QuIC) assay.
In this thesis the revised criteria were validated using a three-year clinicopathological cohort of all neuropathologically-confirmed sCJD cases from the UK. France, Germany and Italy, with a control group with alternative neuropathological diagnoses. The sensitivity and specificity of criteria was compared with prior criteria. Sub-analyses were performed assessing sCJD cases grouped by prion protein genotype, neuropathological classification, disease duration and age.
The revised criteria were found to be 98.5% sensitive, a 21.5% increase from previous criteria, with no loss of specificity. Revisions have led to increases in case ascertainment, including among cases with limited clinical features and atypically long disease duration. This increase in sensitivity is of great utility for prion disease surveillance
- …
