Figure 1 - available via license: Creative Commons Attribution-NonCommercial 4.0 International
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A timeline of human development within the concept that this is very approximate and likely to change with new information which typically causes the lines to move to the left. The definitions of use of tools and social interaction are not defined. Standing and use of tools occurred across different humans (eg, including Neanderthals) but language and social interaction in the last 70 000 years is only clear for Homo sapiens.
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Background
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS.
Methods
Seven hundred and fifty-seven sporadic...
We report an individual with rapidly progressive motor neuron disease (MND), phenotypically compatible with amyotrophic lateral sclerosis (ALS). The patient described in this case report proved positive for human immunodeficiency virus (HIV) and was initiated on antiretroviral therapy (ART). Following ART he clinically stabilised over 10 years and...
Background
Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic facto...
Amyotrophic lateral sclerosis (ALS) commonly referred to as motor neurone disease, is a neurodegenerative disease of unknown pathogenesis that progresses rapidly and has attracted an increased amount of scholarly interest in recent years. The current conception of amyotrophic lateral sclerosis has transitioned into a more complex theory in which in...
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Citations
... [1][2][3] This is seen in Alzheimer's and Parkinson's disease, which have not been observed naturally on a pathological or phenotypic level in non-human species. 1 2 Likewise, unique motor dysfunction in amyotrophic lateral sclerosis (ALS) supports the selective vulnerability of the highly-developed corticomotoneuronal system in humans. [4][5][6] Human-lineage-specific genomic sequences have been shown to be enriched for brain-specific elements and risk loci for neurodegenerative disorders. 7 Thus, while positive natural selection has driven human adaptive evolution, 8 it may be possible that the same selected variants also influence the risk of neurodegenerative disease. ...
Background
Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions.
Methods
We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.
Results
We found a significant depletion of positively-selected SNPs in the heritability of Parkinson’s disease, raising the possibility that these variants may modulate disease risk, in addition to conferring an evolutionary advantage. For Alzheimer’s disease and amyotrophic lateral sclerosis, common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk.
Conclusions
These findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.
... At the ALS end of the spectrum, we uncovered significant atrophy in ALS patients relative to controls centred on bilateral prefrontal and lateral parietal cortex, with right lateralized involvement of the posterior cingulate, motor and insular cortex. Previous emerging literature indicates a cerebral hemispheric dominance, with atrophy predominantly affecting the left motor cortex or dominant cortex in ALS, 42 at least in the early stages of the disease. Right-sided involvement of the cingulate and insular cortices may indicate early emotional processing difficulties 43 as atrophy progresses to extend beyond the motor cortices in ALS. ...
... Previous studies have indicated that ALS commencing in a non-dominant limb tends to spread to the ipsilateral non-dominant limb, whereas that beginning in the dominant side spreads to the contralateral limb at that level. 42 Compared with controls, the ALS group also showed predominant bilateral parietal atrophy. This finding has been suggested to indicate the presence of cases harbouring the C9orf72 gene expansion, although recent studies caution that parietal atrophy is present in both C9orf72 positive and negative cases. ...
The disease syndromes of amyotrophic lateral sclerosis and frontotemporal dementia display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke’s Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant frontotemporal dementia (n = 58) and amyotrophic lateral sclerosis-frontotemporal dementia (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippocampus, amygdala, thalamus, and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-amyotrophic lateral sclerosis patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the amyotrophic lateral sclerosis-frontotemporal dementia and behavioural variant frontotemporal dementia groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76-90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in amyotrophic lateral sclerosis-frontotemporal dementia relative to pure-amyotrophic lateral sclerosis. In contrast, pure-amyotrophic lateral sclerosis displayed significantly greater parietal atrophy. Both behavioural variant frontotemporal dementia and amyotrophic lateral sclerosis-frontotemporal dementia were characterised by volume decrease in the frontal lobes relative to pure-amyotrophic lateral sclerosis. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in amyotrophic lateral sclerosis-frontotemporal dementia compared to pure-amyotrophic lateral sclerosis, and greater left motor cortex and insula atrophy relative to behavioural variant frontotemporal dementia. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum, with key structures including the motor cortex and insula, Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum.
... Many of the earliest clinical observations in ALS reflect features that seem to subserve the dysfunction of an expanded cortical motor system in humans [5][6][7]. The onset of motor weakness is typically focal, but the literature on focality has been largely descriptive of LMN features alone [1,5,8]. ...
... This is partly due to the inherent difficulties of detecting clinical UMN signs, which can be subtle during early disease stages and obscured by severe clinical UMN signs, which can be subtle during early disease stages and obscured by severe muscle wasting in later stages, and partly due to the lack of a universally accepted cortical biomarker [8,9]. As such, the cortical changes underlying clinical weakness have remained challenging to identify in vivo, but they are increasingly postulated as a critical determinator of disease onset and patterns of spread [5,7,10]. Progress in the ability to quantify the UMN lesion is now providing more opportunities to resolve this hypothesis [9,11]. ...
Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes.
... This lack of translation from the SOD1 mouse model to humans with ALS could be a result of differences in pathophysiology. For instance, in SOD1 mice, the loss of motor neurons and associated weakness progresses over a short period 74 , whereas symptoms in humans do not emerge for decades, apparently triggered by a multi-step process that has not yet been replicated in animal models [75][76][77][78][79][80] . ...
Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s — a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.
... In keeping with the present results, it is our experience that clinically observable asymmetry of the tongue is not a feature of ALS. Cerebral hemispheric dominance has been suggested to be a driver of limb asymmetry [36]; interestingly, the hypoglossal nucleus receives bilateral cortical innervation which may limit any such effect in the tongue muscle [37,38]. There do, however, appear to be differences in the impedance spectra obtained from the centre of the tongue versus the lateral portions. ...
Objective:
Electrical impedance myography (EIM) performed on the centre of the tongue shows promise in detecting amyotrophic lateral sclerosis (ALS). Lateral recordings may improve diagnostic performance and provide pathophysiological insights through the assessment of asymmetry. However, it is not known if electrode proximity to the muscle edge, or electrode rotation, distort spectra. We evaluated this using finite element-based modelling.
Approach:
9000 EIM from patients and healthy volunteers were used to develop a finite element model for phase and magnitude. Simulations varied electrode proximity to the muscle edge and electrode rotation. LT-Spice simulations assessed disease effects. Patient data were assessed for reliability, agreement and classification performance.
Main results:
No effect on phase spectra was seen if all electrodes remained in contact with the tissue. Small effects on magnitude were observed. Cole-Cole circuit simulations indicated capacitance reduced with disease severity. Lateral tongue muscle recordings in both patients and healthy volunteers were reproducible and symmetrical. Combined lateral/central tongue EIM improved disease classification compared to either placement alone.
Significance:
Lateral EIM tongue measurements using phase angle are feasible. Such measurements are reliable, find no evidence of tongue muscle asymmetry in ALS and improve disease classification. Lateral measurements enhance tongue EIM in ALS.
... Although the cardinal feature of ALS is degeneration of both upper and lower motor neurons, it is now accepted that ALS is also a disease of the wider brain (3,4). While ALS predominately manifests as motor symptoms, non-motor features, including disorders of sleep and wakefulness, also occur (5)(6)(7)(8)(9)(10). ...
Disorders of sleep and wakefulness are common among neurodegenerative diseases. While amyotrophic lateral sclerosis (ALS) predominately manifests as motor symptoms, there is emerging evidence that disruptions to sleep and wakefulness also occur. This systematic review aims to report the most common disorders of sleep and wakefulness in ALS. We conducted a qualitative systematic review as per PRISMA guidelines and searched literature assessing the association between disorders of sleep and wakefulness with ALS using the PubMed and Medline database. Overall, 50–63% of patients with ALS have poor sleep quality as reported using the Pittsburgh Sleep Quality Index Questionnaire (PSQI). A higher proportion of ALS patients are categorized as poor sleepers, however there is conflicting evidence as to whether patients with ALS are more likely to exhibit excessive daytime sleepiness. Of the studies that utilized polysomnography, all reported various degrees of impairment to sleep microstructure and architecture among ALS patients. In future, longitudinal clinical studies will be essential for establishing the significance of impaired sleep in ALS. Future studies are also needed to establish whether the self-reported measures of poor sleep and impairment to sleep architecture occurs as a direct consequence of the disease, whether they are an early manifestation of the disease, and/or if they contribute to the neurodegenerative process.
... The lack of selection pressure related to the genetic infrastructure that causes ALS can perhaps explain the complexity of the disease. We can consider that the studies claiming that the disease is related to the development process of Homo sapiens can be established in this respect (28,29). If there was a selection pressure, we would expect the neurodegenerative diseases observed in older ages, such as ALS, to eventually disappear in the population. ...
Objective:
Amyotrophic Lateral Sclerosis is one major disease in the group of neurodegenerative conditions. As with most other neurodegenerative diseases, clinical signs of the disease usually show among the elderly population, and most commonly around 60-65 years of age. Therefore the disease is not expected to impact the fertility of ALS patients. When examined from an evolutionary medicine and evolutionary biology perspective, there should be no selection pressure on the patient population due to the late onset of ALS. Methods: In this study, we tested the hypothesis that ALS does not affect fertility on a group of patients with ALS that we collected in a multi-center study. We recruited 511 patients diagnosed with ALS according to the revised El Escorial criteria, and 236 control cases without a neurodegenerative disease. We compared the ALS group's number of offspring with the control group in three consecutive generations. Results: No statistically significant difference was found between the number of siblings of ALS and control groups (p = 0.44). A statistically significant difference was found between the number of children of ALS and control groups (p < 0.001), indicating ALS patients had more children than controls. When the number of children is assessed by gender, for women, there was no statistically significant difference between the number of children of ALS and control groups (p = 0.067). Conclusions: This finding supports the view that ALS does not have a negative selection pressure on the patient population's fertility.
The intricate relationship between physiological and pathological aggregation in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), poses a significant research question. Comprehending the role of liquid–liquid phase separation (LLPS) and the toxicity of TDP-43 aggregation is of critical importance. This necessitates a comprehensive understanding of the multifarious factors involved in LLPS, including the regulation of TDP-43 intrinsically disordered regions (IDRs), isoforms, oligomers, aggregations, and interactions with RNA and other ALS-related proteins. Additionally, investigating the association between nervous system specificity and condensate formation in neurodegenerative diseases is essential. To develop effective therapies for neurodegenerative diseases, a thorough understanding of intracellular condensates and their roles is imperative.
Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions. We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease . We found no evidence for enrichment of positively-selected SNPs in the heritability of Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, suggesting that common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk. These findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.
Amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) are neurodegenerations with evolutionary underpinnings, expansive clinical presentations, and multiple genetic risk factors involving a complex network of pathways. This perspective considers the complex cellular pathology of aging motoneuronal and frontal/prefrontal cortical networks in the context of evolutionary, clinical, and biochemical features of the disease. We emphasize the importance of evolution in the development of the higher cortical function, within the influence of increasing lifespan. Particularly, the role of aging on the metabolic competence of delicately optimized neurons, age-related increased proteostatic costs, and specific genetic risk factors that gradually reduce the energy available for neuronal function leading to neuronal failure and disease.
