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.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor function, with additional evidence of extensive nonmotor involvement. Despite increasing recognition of the disease as a multisystem network disorder characterised by impaired connectivity, the precise neuroelectric characteristics of impaired cortical communication remain to be fully elucidated. Here, we characterise changes in functional connectivity using beamformer source analysis on resting‐state electroencephalography recordings from 74 ALS patients and 47 age‐matched healthy controls. Spatiospectral characteristics of network changes in the ALS patient group were quantified by spectral power, amplitude envelope correlation (co‐modulation) and imaginary coherence (synchrony). We show patterns of decreased spectral power in the occipital and temporal (δ‐ to β‐band), lateral/orbitofrontal (δ‐ to θ‐band) and sensorimotor (β‐band) regions of the brain in patients with ALS. Furthermore, we show increased co‐modulation of neural oscillations in the central and posterior (δ‐, θ‐ and γl‐band) and frontal (δ‐ and γl‐band) regions, as well as decreased synchrony in the temporal and frontal (δ‐ to β‐band) and sensorimotor (β‐band) regions. Factorisation of these complex connectivity patterns reveals a distinct disruption of both motor and nonmotor networks. The observed changes in connectivity correlated with structural MRI changes, functional motor scores and cognitive scores. Characteristic patterned changes of cortical function in ALS signify widespread disease‐associated network disruption, pointing to extensive dysfunction of both motor and cognitive networks. These statistically robust findings, that correlate with clinical scores, provide a strong rationale for further development as biomarkers of network disruption for future clinical trials.

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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.

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Amyotrophic lateral sclerosis (ALS) encompasses a heterogeneous group of phenotypes with different progression rates, varying degree of extra-motor involvement and divergent progression patterns. The natural history of ALS is increasingly evaluated by large, multi-time point longitudinal studies, many of which now incorporate presymptomatic and post-mortem assessments. These studies not only have the potential to characterize patterns of anatomical propagation, molecular mechanisms of disease spread, but also to identify pragmatic monitoring markers. Sensitive markers of progressive neurodegenerative change are indispensable for clinical trials and individualized patient care. Biofluid markers, neuroimaging indices, electrophysiological markers, rating scales, questionnaires, and other disease-specific instruments have divergent sensitivity profiles. The discussion of candidate monitoring markers in ALS has a dual academic and clinical relevance, and is particularly timely given the increasing number of pharmacological trials. The objective of this paper is to provide a comprehensive and critical review of longitudinal studies in ALS, focusing on the sensitivity profile of established and emerging monitoring markers.

Post-polio syndrome (PPS) is a neurological condition that affects polio survivors decades after their initial infection. Despite its high prevalence, the etiology of PPS remains elusive, mechanisms of progression are poorly understood, and the condition is notoriously under-researched. While motor dysfunction is a hallmark feature of the condition, generalized fatigue, sleep disturbance, decreased endurance, neuropsychological deficits, sensory symptoms, and chronic pain are also often reported and have considerable quality of life implications in PPS. The non-motor aspects of PPS are particularly challenging to evaluate, quantify, and treat. Generalized fatigue is one of the most distressing symptoms of PPS and is likely to be multifactorial due to weight-gain, respiratory compromise, poor sleep, and polypharmacy. No validated diagnostic, monitoring, or prognostic markers have been developed in PPS to date and the mainstay of therapy centers on symptomatic relief and individualized rehabilitation strategies such as energy conservation and muscle strengthening exercise regimes. Despite a number of large clinical trials in PPS, no effective disease-modifying pharmacological treatments are currently available.