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IntroductionALS functional rating scale (revised) (ALSFRS-R) is the most widely used functional rating system in patients with amyotrophic lateral sclerosis (ALS). However, heterogeneity in ALSFRS-R progression renders analysis challenging. We have explored the characteristics of total ALSFRS-R, and ALSFRS-R subscores in longitudinal and survival models, to determine whether subscore analysis enhances the precision of the instrument.MethodsAll cases with ALSFRS-R scores on the Irish ALS register were included. ALSFRS-R subscores were defined for bulbar, motor and respiratory domains. Longitudinal models were used to visualise fitted total ALSFRS-R and ALSFRS-R subscore progression. In addition, the prognostic value of convenience and computed ALSFRS-R slope and subscore slopes were compared.Results407 incident cases were identified with a complete ALSFRS-R measure. 233 (57%) patients were male, and 125 (31%) had bulbar-onset disease. ALSFRS-R bulbar and motor subscore slopes provided a better fit in prognostic models when combined over the total ALSFRS-R slope. Longitudinal analysis revealed that the ALSFRS-R motor subscore deteriorated earlier in spinal-onset disease over bulbar-onset disease, while in bulbar-onset disease the ALSFRS-R bulbar subscore deteriorated earlier and faster than in spinal-onset disease.DiscussionOur analysis builds on previous knowledge of ALSFRS-R subscores. Decline in ALSFRS-R motor subscores in patients with spinal-onset disease, and decline in ALSFRS-R bulbar subscores in patients with bulbar-onset disease, may predate reported disease onset dates. Respiratory subscores were not prognostically informative after adjustment for bulbar and motor subscores. These results provide robust evidence that the ALSFRS-R should not be reported as a single combined score, but rather as domain specific subscores.

BackgroundAmyotrophic lateral sclerosis (ALS) is often associated with cognitive and/or behavioural impairment. Cognitive reserve (CR) may play a protective role in offsetting cognitive impairment. This study examined the relationship between CR and longitudinal change in cognition in an Irish ALS cohort.MethodsLongitudinal neuropsychological assessment was carried out on 189 patients over 16 months using the Edinburgh cognitive and behavioural ALS screen (ECAS) and an additional battery of neuropsychological tests. CR was measured by combining education, occupation and physical activity data. Joint longitudinal and time-to-event models were fitted to investigate the associations between CR, performance at baseline and decline over time while controlling for non-random drop-out.ResultsCR was a significant predictor of baseline neuropsychological performance, with high CR patients performing better than those with medium or low CR. Better cognitive performance in high CR individuals was maintained longitudinally for ECAS, social cognition, executive functioning and confrontational naming. Patients displayed little cognitive decline over the course of the study, despite controlling for non-random drop-out.ConclusionsThese findings suggest that CR plays a role in the presentation of cognitive impairment at diagnosis but is not protective against cognitive decline. However, further research is needed to examine the interaction between CR and other objective correlates of cognitive impairment in ALS.

Amyotrophic lateral sclerosis, a devastating neurodegenerative disease, is characterized by the progressive loss of motor neurons and the accumulation of misfolded protein aggregates. The latter suggests impaired proteostasis may be a key factor in disease pathogenesis, though the underlying mechanisms leading to the accumulation of aggregates is unclear. Further, recent studies have indicated that motor neuron cell death may be mediated by astrocytes. Herein we demonstrate that ALS patient iPSC-derived astrocytes modulate the autophagy pathway in a non-cell autonomous manner. We demonstrate cells treated with patient derived astrocyte conditioned medium demonstrate decreased expression of LC3-II, a key adapter protein required for the selective degradation of p62 and ubiquitinated proteins targeted for degradation. We observed an increased accumulation of p62 in cells treated with patient conditioned medium, with a concomitant increase in the expression of SOD1, a protein associated with the development of ALS. Activation of autophagic mechanisms with Rapamycin reduces the accumulation of p62 puncta in cells treated with patient conditioned medium. These data suggest that patient astrocytes may modulate motor neuron cell death by impairing autophagic mechanisms, and the autophagy pathway may be a useful target in the development of novel therapeutics.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological condition that requires coordinated, multidisciplinary clinical management. ALS is prone to misdiagnosis as its signs and symptoms may be non-specific, which may prolong patients' journey to multidisciplinary ALS care. Using chart review and national register data, we have detailed the journey of a national cohort of ALS patients (n = 155) from the time of first symptom to presentation at a multidisciplinary clinic (MDC). Key milestones were analysed, including frequency of consultations, clinical interventions, and associated economic cost. A majority of patients was male (60%), 65 years of age and over (54%), and had spinal onset ALS (72%). Time from onset of first symptoms to ALS diagnosis was a mean of 15.1 months (median, 11). There was a mean interval of 17.4 months (median 12.5) from first symptoms to arrival at the MDC, and a mean of 4.09 (median, 4) consultations with health care professionals. Electromyography and nerve conduction studies were among the most common interventions. Direct referral by a general practitioner (GP) to a neurologist was associated with reduced cost, but not reduced diagnostic delay. Bulbar ALS was associated with shorter time from symptom onset to diagnosis. Neurologist consultation in the first three consultations was associated with lower costs prior to the ALS clinic attendance but not a shorter time from first symptom to final diagnosis. Mean cost prior to attending the MDC was €3,486 per patient. Expedited referral to the multidisciplinary ALS clinic would have reduced costs by an estimated €2,072 per patient. Development of a standardised pathway with early referral to neurology of patients with suspected symptoms of ALS could limit unnecessary interventions and reduce cost of care.

There has been much interest in spatial analysis of ALS to identify potential environmental or genetically caused clusters of disease. Results to date have been inconclusive. The Irish ALS register has been recently geocoded, presenting opportunity to perform a spatial analysis on national prospectively gathered data of incident cases over an 18-year period. 1,645 cases of ALS in Ireland from January 1995 to July 2013 were identified from the Irish ALS register. 1,638 cases were successfully geocoded. Census data from four censuses: 1996, 2002, 2006 & 2011 were used to calculate an average population for the period and standardized incidence rates (SIRs) were calculated for 3,355 areas (Electoral Divisions). Bayesian conditional auto-regression was applied to produce smoothed relative risks (RR). These were then mapped for all cases, males & females separately, and those under 55 vs over 55 at diagnosis. Bayesian and linear regression were used to examine the relationship between population density and RR. Smoothed maps revealed no overall geographical pattern to ALS incidence in Ireland, although several areas of localized increased risk were identified. Stratified maps also suggested localized areas of increased RR, while dual analysis of the relationship between population density and RR of ALS yielded conflicting results, linear regression revealed a weak relationship. In contrast to some previous studies our analysis did not reveal any large-scale geographic patterns of incidence, yet localized areas of moderately high risk were found in both urban and rural areas. Stratified maps by age revealed a larger number of cases in younger people in the area of County Cork--possibly of genetic cause. Bayesian auto-regression of population density failed to find a significant association with risk, however weighted linear regression of post Bayesian smoothed Risk revealed an association between population density and increased ALS risk.

ObjectiveCerebellar disease burden and cerebro-cerebellar connectivity alterations are poorly characterised in amyotrophic lateral sclerosis (ALS) despite the likely contribution of cerebellar pathology to the clinical heterogeneity of the condition.MethodsA prospective imaging study has been undertaken with 271 participants to systematically evaluate cerebellar grey and white matter alterations, cerebellar peduncle integrity and cerebro-cerebellar connectivity in ALS. Participants were stratified into four groups: (1) patients testing positive for GGGGCC repeat expansions in C9orf72, (2) patients carrying an intermediate-length repeat expansion in ATXN2, (3) patients without established ALS-associated mutations and (4) healthy controls. Additionally, the cerebellar profile of a single patient with ALS who had an ATXN2 allele length of 62 was evaluated. Cortical thickness, grey matter and white matter volumes were calculated in each cerebellar lobule complemented by morphometric analyses to characterise genotype-associated atrophy patterns. A Bayesian segmentation algorithm was used for superior cerebellar peduncle volumetry. White matter diffusivity parameters were appraised both within the cerebellum and in the cerebellar peduncles. Cerebro-cerebellar connectivity was assessed using deterministic tractography.ResultsCerebellar pathology was confined to lobules I–V of the anterior lobe in patients with sporadic ALS in contrast to the considerable posterior lobe and vermis disease burden identified in C9orf72 mutation carriers. Patients with intermediate ATXN2 expansions did not exhibit significant cerebellar pathology.ConclusionsFocal rather than global cerebellar degeneration characterises ALS. Pathognomonic ALS symptoms which are typically attributed to other anatomical regions, such as dysarthria, dysphagia, pseudobulbar affect, eye movement abnormalities and cognitive deficits, may be modulated, exacerbated or partially driven by cerebellar changes in ALS.

Background Bulbar dysfunction is a cardinal feature of ALS with important quality of life and management implications. The objective of this study is the longitudinal evaluation of a large panel imaging metrics pertaining to bulbar dysfunction, encompassing cortical measures, structural and functional cortico-medullary connectivity indices and brainstem metrics. Methods A standardised, multimodal imaging protocol was implemented with clinical and genetic profiling to systematically appraise the biomarker potential of specific metrics. A total of 198 patients with ALS and 108 healthy controls were included. Results Longitudinal analyses revealed progressive structural and functional disconnection between the motor cortex and the brainstem over time. Cortical thickness reduction was an early feature on cross-sectional analyses with limited further progression on longitudinal follow-up. Receiver operating characteristic analyses of the panel of MR metrics confirmed the discriminatory potential of bulbar imaging measures between patients and controls and area-under-the-curve values increased significantly on longitudinal follow-up. C9orf72 carriers exhibited lower brainstem volumes, lower cortico-medullary structural connectivity and faster cortical thinning. Sporadic patients without bulbar symptoms, already exhibit significant brainstem and cortico-medullary connectivity alterations. Discussion Our results indicate that ALS is associated with multi-level integrity change from cortex to brainstem. The demonstration of significant corticobulbar alterations in patients without bulbar symptoms confirms considerable presymptomatic disease burden in sporadic ALS. The systematic assessment of radiological measures in a single-centre academic study helps to appraise the diagnostic and monitoring utility of specific measures for future clinical and clinical trial applications.

BackgroundPrimary lateral sclerosis is a progressive upper-motor-neuron disorder associated with markedly longer survival than ALS. In contrast to ALS, the genetic susceptibility, histopathological profile and imaging signature of PLS are poorly characterised. Suspected PLS patients often face considerable diagnostic delay and prognostic uncertainty.ObjectiveTo characterise the distinguishing clinical, genetic and imaging features of PLS in contrast to ALS and healthy controls.MethodsA prospective population-based study was conducted with 49 PLS patients, 100 ALS patients and 100 healthy controls using genetic profiling, standardised clinical assessments and neuroimaging. Whole-brain and region-of-interest analyses were undertaken to evaluate patterns of grey and white matter degeneration.ResultsIn PLS, disease burden in the motor cortex is more medial than in ALS consistent with its lower limb symptom-predominance. PLS is associated with considerable cerebellar white and grey matter degeneration and the extra-motor profile of PLS includes marked insular, inferior frontal and left pars opercularis pathology. Contrary to ALS, PLS spares the postcentral gyrus. The body and splenium of the corpus callosum are preferentially affected in PLS, in contrast to the genu involvement observed in ALS. Clinical measures show anatomically meaningful correlations with imaging metrics in a somatotopic distribution. PLS patients tested negative for C9orf72 repeat expansions, known ALS and HSP-associated genes.ConclusionsMultiparametric imaging in PLS highlights disease-specific motor and extra-motor involvement distinct from ALS. In a condition where limited post-mortem data are available, imaging offers invaluable pathological insights. Anatomical correlations with clinical metrics confirm the biomarker potential of quantitative neuroimaging in PLS.

The contribution of cerebellar pathology to cognitive and behavioural manifestations is increasingly recognised, but the cerebellar profiles of FTD phenotypes are relatively poorly characterised. A prospective, single-centre imaging study has been undertaken with a high-resolution structural and diffusion tensor protocol to systematically evaluate cerebellar grey and white matter alterations in behavioural-variant FTD(bvFTD), non-fluent variant primary progressive aphasia(nfvPPA), semantic-variant primary progressive aphasia(svPPA), C9orf72-positive ALS-FTD(C9 + ALSFTD) and C9orf72-negative ALS-FTD(C9-ALSFTD). Cerebellar cortical thickness and complementary morphometric analyses were carried out to appraise atrophy patterns controlling for demographic variables. White matter integrity was assessed in a study-specific white matter skeleton, evaluating three diffusivity metrics: fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Significant cortical thickness reductions were identified in: lobule VII and crus I in bvFTD; lobule VI VII, crus I and II in nfvPPA; and lobule VII, crus I and II in svPPA; lobule IV, VI, VII and Crus I and II in C9 + ALSFTD. Morphometry revealed volume reductions in lobule V in all groups; in addition to lobule VIII in C9 + ALSFTD; lobule VI, VIII and vermis in C9-ALSFTD; lobule V, VII and vermis in bvFTD; and lobule V, VI, VIII and vermis in nfvPPA. Widespread white matter alterations were demonstrated by significant fractional anisotropy, axial diffusivity and radial diffusivity changes in each FTD phenotype that were more focal in those with C9 + ALSFTD and svPPA. Our findings indicate that FTD subtypes are associated with phenotype-specific cerebellar signatures with the selective involvement of specific lobules instead of global cerebellar atrophy.

Frontotemporal dementia (FTD) phenotypes have distinctive and well-established cortical signatures, but their subcortical grey matter profiles are poorly characterised. The comprehensive characterisation of striatal and thalamic pathology along the ALS-FTD spectrum is particularly timely, as dysfunction of frontostriatal and cortico-thalamic networks contribute to phenotype-defining cognitive, behavioral, and motor deficits. Ten patients with behavioral-variant FTD, 11 patients with non-fluent-variant primary progressive aphasia, 5 patients with semantic-variant primary progressive aphasia, 14 ALS-FTD patients with C9orf72 hexanucleotide expansions, 12 ALS-FTD patients without hexanucleotide repeats, 36 ALS patients without cognitive impairment and 50 healthy controls were included in a prospective neuroimaging study. Striatal, thalamic, hippocampal and amygdala pathology was evaluated using volume measurements, density analyses and connectivity-based segmentation. Significant volume reductions were identified in the thalamus and putamen of non-fluent-variant PPA patients. Marked nucleus accumbens and hippocampal atrophy was observed in the behavioral-variant FTD cohort. Semantic-variant PPA patients only exhibited volumetric changes in the left hippocampus. C9-positive ALS-FTD patients showed preferential density reductions in thalamic sub-regions connected to motor and sensory cortical areas. C9-negative ALS-FTD patients exhibited striatal pathology in sub-regions projecting to rostral-motor and executive cortical areas. The bulk of striatal and thalamic pathology in non-fluent-variant PPA patients was identified in foci projecting to motor areas. Subcortical density alterations in svPPA patients were limited to basal ganglia regions with parietal projections. Striatal and thalamic changes in FTD exhibit selective, network-defined vulnerability patterns mirroring cortical pathology. Multi-modal cortico-basal imaging analyses confirm that the subcortical grey matter profiles of FTD phenotypes are just as distinct as their cortical signatures. Our findings support emerging concepts of network-wise degeneration, preferential circuit vulnerability and disease propagation along connectivity patterns.