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The presymptomatic phase of amyotrophic lateral sclerosis (ALS) has long been of academic interest, but with the emergence of antisense oligonucleotide therapies,1 the characterisation of presymptomatic disease burden has now gained practical relevance. While radiological2 3 and electrophysiological4 alterations have previously been described in asymptomatic mutations carriers, Lule et al 5 have conducted a particularly elegant longitudinal study using a comprehensive neuroimaging-neuropsychology protocol. Her team identified considerable orbitofrontal white matter changes, verbal fluency and memory deficits in seemingly asymptomatic GGGGCC hexanucleotide repeat carriers in their 40s. Given the accruing evidence that marked radiological changes can be observed in C9orf72 hexanucleotide carriers by the time they reach 40 despite the detection limitations of our current imaging modalities, …

Background Recent quantitative neuroimaging studies have been successful in capturing phenotype and genotype-specific changes in dementia syndromes, amyotrophic lateral sclerosis, Parkinson9s disease and other neurodegenerative conditions. However, the majority of imaging studies are cross-sectional, despite the obvious superiority of longitudinal study designs in characterising disease trajectories, response to therapy, progression rates and evaluating the presymptomatic phase of neurodegenerative conditions. Objectives The aim of this work is to perform a systematic review of longitudinal imaging initiatives in neurodegeneration focusing on methodology, optimal statistical models, follow-up intervals, attrition rates, primary study outcomes and presymptomatic studies. Methods Longitudinal imaging studies were identified from ‘PubMed’ and reviewed from 1990 to 2014. The search terms ‘longitudinal’, ‘MRI’, ‘presymptomatic’ and ‘imaging’ were utilised in combination with one of the following degenerative conditions; Alzheimer9s disease, amyotrophic lateral sclerosis/motor neuron disease, frontotemporal dementia, Huntington9s disease, multiple sclerosis, Parkinson9s disease, ataxia, HIV, alcohol abuse/dependence. Results A total of 423 longitudinal imaging papers and 103 genotype-based presymptomatic studies were identified and systematically reviewed. Imaging techniques, follow-up intervals and attrition rates showed significant variation depending on the primary diagnosis. Commonly used statistical models included analysis of annualised percentage change, mixed and random effect models, and non-linear cumulative models with acceleration–deceleration components. Discussion and conclusions Although longitudinal imaging studies have the potential to provide crucial insights into the presymptomatic phase and natural trajectory of neurodegenerative processes a standardised design is required to enable meaningful data interpretation.

Amyotrophic lateral sclerosis (ALS) has distinctive and well-established radiological signatures which are increasingly utilised in advanced machine-learning algorithms heralding exciting novel diagnostic applications.1 2 Quantitative spinal cord (SC) imaging provides a unique opportunity to evaluate both upper (UMN) and lower motor neuron (LMN) involvement, and recent studies have showcased its biomarker potential in ALS through reliable cross-sectional area (CSA) measurements, evaluation of diffusion tensor imaging (DTI) parameters, correlations with clinical measures and survival.3 4 Nevertheless, no studies have evaluated the diagnostic accuracy of SC metrics in ALS to date. Accordingly, the objective of this study was to evaluate the effectiveness of multimodal cervical imaging in distinguishing ALS from healthy controls (HC) using a random forest (RF) classification algorithm.5 Sixty patients with ALS and 45 age-matched controls gave informed consent to participate in a prospective neuroimaging study in the Pitie-Salpetriere Hospital in Paris. Participating patients had probable or definite ALS according to the revised El-Escorial criteria. Patients with cognitive impairment, relevant comorbidities and taking medications other than riluzole were excluded from the study. ### MRI Cervical cord data were acquired from C2 to C7 on a 3T MRI system (Siemens TIM Trio). A T2-weighted three-dimensional turbo spin echo protocol was used for structural imaging with an isotropic voxel size 0.9×0.9×0.9 mm3, field of view (FOV)=280×280 mm2, 52 sagittal slices, repetition time (TR)=1500 ms, echo time (TE)=120 ms and acceleration factor=3. DTI data were acquired using a single-shot echo-planar imaging sequence. The acquisition was cardiac gated with a voxel size=1×1×5 mm3, FOV=128×128 mm2, TR=700 ms, TE=96 ms, acceleration factor=2, b value=1000 s/mm2, 64 diffusion encoding directions and four averages. 3D gradient echo images were used …

Background Body region of onset and functional disability are key components of disease heterogeneity in amyotrophic lateral sclerosis (ALS). Objectives To evaluate patterns of grey matter pathology in the motor cortex and correlate focal structural changes with functional disability. Methods We conducted a single-centre neuroimaging study of a cohort of 33 cognitively normal patients with amyotrophic lateral sclerosis (ALS) and 44 healthy controls. A voxel-wise generalised linear model was used to investigate the distribution of disease burden within the motor cortex in relation to clinical disability. Results Patients with bulbar onset have bilateral focal atrophy in the bulbar segment of the motor homunculus compared with patients with limb onset who have focal cortical changes in the limb segment of their motor strip. Furthermore, the extent to which different body regions are affected in ALS corresponds to the extent of focal grey matter loss in the primary motor cortex. Cortical ALS pathology also extends beyond the motor cortex affecting frontal, occipital and temporal regions. Conclusions Focal grey matter atrophy within the motor homunculus corresponds with functional disability in ALS. The findings support the existing concepts of cortical focality and motor phenotype heterogeneity in ALS.

Background Despite considerable interest, the population-based frequency, clinical characteristics and natural history of cognitive impairment in amyotrophic lateral sclerosis (ALS) are not known. Methodology The authors undertook a prospective population-based study of cognitive function in 160 incident Irish ALS patients and 110 matched controls. Home-based visits were conducted to collect demographic and neuropsychological data. Patients were classified using the recently published consensus criteria and by a domain-based classification of both executive and non-executive cognitive processes. Results 13.8% of patients fulfilled the Neary criteria for frontotemporal dementia. In addition, 34.1% of ALS patients without evidence of dementia fulfilled the recently published consensus criteria for cognitive impairment. Non-demented ALS patients had a significantly higher frequency of impairment in language and memory domains compared to healthy controls. These deficits occurred primarily in patients with executive dysfunction. 14% of ALS patients had evidence of cognitive impairment without executive dysfunction, and no cognitive abnormality was detected in almost half the cohort (46.9%). Conclusion Co-morbid dementia occurs in approximately 14% of patients with a new diagnosis of ALS. Cognitive impairment, predominantly but not exclusively in the form executive dysfunction, is present in more than 40% of ALS patients who have no evidence of dementia. Cognitive impairment in ALS is not a universal feature, and its manifestations may be more heterogeneous than previously recognised.

Background Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition. Optimal management requires a palliative approach from diagnosis with emphasis on patient autonomy, dignity and quality of life. Objective To conduct a systematic analysis of the type, level and timing of specialist palliative care intervention in ALS. Results Despite an international consensus that ALS management should adopt a multidisciplinary approach, integration of palliative care into ALS management varies considerably across health care systems. Late referral to palliative services in ALS is not uncommon and may impact negatively on the quality of life of ALS patients and their caregivers. However, common themes and principles of engagement can be identified across different jurisdictions, and measurement systems have been established that can assess the impact of palliative care intervention. Conclusions There is considerable evidence that palliative care intervention improves quality of life in patients and carers. International consensus guidelines would assist in the development of a framework for active palliative care engagement in ALS and other neurodegenerative diseases.

The identification of a core spatial pattern of white matter pathology in amyotrophic lateral sclerosis (ALS) is essential for the development of MRI-based diagnostic protocols. However, the description of disease-defining white matter changes is confounded by the genetic, neuropsychological and clinical heterogeneity of ALS. Over 50 diffusion tensor imaging (DTI) papers have been published in ALS to date, and while corticospinal tract and corpus callosum involvement is invariably highlighted, DTI studies are conflicting regarding the degree of extramotor and cerebellar white matter degeneration. Nonetheless, there is an evolving recognition that motor disability in ALS is complicated by extrapyramidal dysfunction1 and cerebellar involvement.2 The notion, that cerebellar pathology may contribute to non-motor manifestations, such as impairments in language, attention and social cognition, is also increasingly recognised.3 Recently, cerebellar changes in ALS and frontotemporal lobar degeneration (FTLD) have been specifically linked with the C9orf72 hexanucleotide repeat expansion,4 raising the question whether cerebellar degeneration is an important feature of C9orf72 negative ALS. In order to evaluate cerebellar white matter involvement in ALS, a comprehensive DTI study has been carried out with 42 healthy controls, 27 cognitively intact C9orf72 negative patients with ALS, and nine patients with ALS carrying the C9orf72 hexanucleotide expansion. All patients tested negative for a panel of other gene mutations implicated in ALS, including FUS , SOD1 , TARDBP , ANG , VAPB , VCP , OPTN , SETX and ALS2 . All three study groups were matched for age and patient groups were matched for disease duration: C9orf72 negative ALS group (n=27, mean age 59.7 (SD 10.6), gender 13M/14F, mean disease duration 26.7 (SD 23) months), C9orf72 positive ALS group (n=9, mean age …