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Cognitive test scores in ALS and PLS patients. a DRS-2 total raw scores for each patient. Values above 133 (dashed line) are considered normal according to reference values. b Scaled scores for the five domains of the DRS-2. Group means ± SD are shown. The DRS-2 scaled scores were significantly less in ALS patients than in PLS patients (ANOVA, p < 0.001). c, d Scaled scores on selected D-KEFS subtests for ALS patients (c) and PLS patients (d) fulfilling the consensus criteria for cognitive impairment (ALSci) compared to patients without cognitive impairment (means ± SD).
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Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor i...
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Context 1
... ALS and 23 PLS patients completed all portions of the DRS-2. The propor- tion of patients who scored below normal (DRS-2 raw score <133) was higher in the ALS patient group (35%) than in the PLS patient group (5%; p = 0.022, Fisher's exact test; fig. 2 a). The lower scores occurred across all five subscores of the DRS-2, including those, such as conceptualization, that do not rely on motor function (ANOVA F = 17.04, p < 0.001; fig. 2 b). No patient met the criteria for FTLD of Neary et al. [4] . Table 2 shows the number of patients completing each test in the D-KEFS battery. There was ...Context 2
... who scored below normal (DRS-2 raw score <133) was higher in the ALS patient group (35%) than in the PLS patient group (5%; p = 0.022, Fisher's exact test; fig. 2 a). The lower scores occurred across all five subscores of the DRS-2, including those, such as conceptualization, that do not rely on motor function (ANOVA F = 17.04, p < 0.001; fig. 2 b). No patient met the criteria for FTLD of Neary et al. [4] . Table 2 shows the number of patients completing each test in the D-KEFS battery. There was no difference between the PLS and ALS patient groups in the mean scaled scores for any D-KEFS subtest ( table 2 ). However, 9 ALS and 2 PLS patients individually met the criteria for ...Similar publications
Cognitive deficits in brain tumours are generally thought to be relatively mild and nonspecific, although recent evidence challenges this notion. One possibility is that cognitive screening tools are being used to assess cognitive functions but their sensitivity to detect cognitive impairment may be limited. For improved sensitivity to recognise mi...
Citations
... These findings supported a cerebro-cerebellar connectivity disruption which probably contributes to the motor disability in PLS. Other DTI studies have specifically highlighted extra-corpus callosum diffusivity alterations involving the superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes [112,113]. At variance from ALS, there is a relative lack of longitudinal imaging studies in PLS. ...
Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.
... 9 However, assessing global EF with standardized combinations of tests such as the Delis Kaplan Executive Function System (D-KEFS) may lead to an overestimation of EF impairment. [10][11][12] Furthermore, these neuropsychological batteries are long and especially burdensome for cognitively impaired patients to complete. Additionally, they are vulnerable to non-cognitive factors, such as motor impairment, which can affect participant performance and confound the interpretation of results. ...
Objective:
Cognitive contributions to decisional capacity are complex and not well understood. Capacity to consent for research has been linked to executive function, but executive function assessment tools are imperfect. In this study, we examine the relationship between decisional capacity and a newly developed executive function composite score and determine whether cognitive performance can predict impaired decisional capacity.
Methods:
This is a cross sectional study of participants at the National Institutes of Health with frontotemporal dementia-amyotrophic lateral sclerosis spectrum disorders enrolled between 2017 and 2022. A structured interview tool was used to ascertain research decisional capacity. Study participant Uniform Data Set (v3.0) executive function (UDS3-EF) composite score, Clinical Dementia Rating Scale©, and Neuropsychiatric Inventory was determined.
Results:
A decrease in UDS3-EF composite score significantly increased the odds of impaired decisional capacity (OR = 2.92, 95% CI [1.66-5.13], p = 0.0002). Executive function was most impaired in frontotemporal dementia (-2.86, SD = 1.26) and least impaired in amyotrophic lateral sclerosis (-0.52, SD = 1.25) participants. The UDS3-EF composite score was also strongly correlated to the Clinical Dementia Rating Scale©.
Interpretation:
Decisional capacity is intrinsically related to executive function in neurodegenerative disorders, and executive dysfunction may predict a lack of decisional capacity alerting investigators of the need for additional scrutiny during the informed consent process.
... Moreover, positive correlations with disease progression rate and symptom duration suggest higher neuronal synchronization is linearly associated with an average disease progression rate and severity of clinical symptoms [96,97]. Last, Rs-FC in the left fronto-parietal RSN was associated with cognitive performance (ECAS Total) indicating that the underlying neural mechanism might be analogous to the dysfunctions of frontal and parietal brain regions [79,[98][99][100][101]. Overall, the present findings suggest that functional connectivity in the fronto-parietal network is crucial for instantiating and flexibly modulating cognitive control [102]. ...
Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive degeneration of upper motor neurons and lower motor neurons, and frontotemporal regions resulting in impaired bulbar, limb, and cognitive function. Magnetic resonance imaging studies have reported cortical and subcortical brain involvement in the pathophysiology of ALS. The present study investigates the functional integrity of resting-state networks (RSNs) and their importance in ALS. Intra- and inter-network resting-state functional connectivity (Rs-FC) was examined using an independent component analysis approach in a large multi-center cohort. A total of 235 subjects (120 ALS patients; 115 healthy controls (HC) were recruited across North America through the Canadian ALS Neuroimaging Consortium (CALSNIC). Intra-network and inter-network Rs-FC was evaluated by the FSL-MELODIC and FSLNets software packages. As compared to HC, ALS patients displayed higher intra-network Rs-FC in the sensorimotor, default mode, right and left fronto-parietal, and orbitofrontal RSNs, and in previously undescribed networks including auditory, dorsal attention, basal ganglia, medial temporal, ventral streams, and cerebellum which negatively correlated with disease severity. Furthermore, ALS patients displayed higher inter-network Rs-FC between the orbitofrontal and basal ganglia RSNs which negatively correlated with cognitive impairment. In summary, in ALS there is an increase in intra- and inter-network functional connectivity of RSNs underpinning both motor and cognitive impairment. Moreover, the large multi-center CALSNIC dataset permitted the exploration of RSNs in unprecedented detail, revealing previously undescribed network involvement in ALS.
... On neuroimaging, dorsal column degeneration [9,57,58], thalamic pathology [59,60] and postcentral gyrus [61,62] atrophy have consistently been reported. Structural [63], diffusion [64], functional [65], susceptibility [66], and MR spectroscopy [67] have all captured some degree of parietal and occipital lobe involvement. Despite these reports, there is a prevailing notion that ALS spares sensory networks [68], and no dedicated cerebral studies have systematically investigated the cortical, subcortical and white matter components of sensory pathways. ...
Background:
While amyotrophic lateral sclerosis (ALS) is widely recognised as a multi-network disorder with extensive frontotemporal and cerebellar involvement, sensory dysfunction is relatively under evaluated. Subtle sensory deficits have been sporadically reported, but there is a prevailing notion that sensory pathways may be relatively spared in ALS.
Methods:
In a prospective neuroimaging study we have systematically evaluated cerebral grey and white matter structures involved in the processing, relaying and mediation of sensory information. Twenty two C9orf72 positive ALS patients (C9+ ALS), 138 C9orf72 negative ALS patients (C9- ALS) and 127 healthy controls were included.
Results:
Widespread cortical alterations were observed in C9+ ALS including both primary and secondary somatosensory regions. In C9- ALS, cortical thickness reductions were observed in the postcentral gyrus. Thalamic nuclei relaying somatosensory information as well as the medial and lateral geniculate nuclei exhibited volume reductions. Diffusivity indices revealed posterior thalamic radiation pathology and a trend of left medial lemniscus degeneration was also observed in C9- ALS (p = 0.054). Our radiology data confirm the degeneration of somatosensory, visual and auditory pathways in ALS, which is more marked in GGGGCC hexanucleotide repeat expansion carriers.
Conclusions:
In contrast to the overwhelming focus on motor system degeneration and frontotemporal dysfunction in recent research studies, our findings confirm that sensory circuits are also affected in ALS. The involvement of somatosensory, auditory and visual pathways in ALS may have important clinical ramifications which are easily overlooked in the context of unremitting motor decline. Subtle sensory deficits may exacerbate mobility, contribute to fall risk, impair dexterity, and worsen bulbar dysfunction, therefore comprehensive sensory testing should also be performed as part of the clinical assessments in ALS.
... Moreover, more than 50% of ALS show cognitive impairment [28][29][30][31] which is not restricted to traditional frontal-related executive dysfunction [32][33][34] and corroborates with structural and functional alterations in cross-sectional and longitudinal MRI studies [7,[35][36][37][38][39][40][41][42][43]. In addition, other MND phenotypes present variable changes across different cognitive functions [44,45] in line with neuroimaging findings [46][47][48][49][50][51]. However, neurometabolic changes in extra-motor regions are only seldom examined and mainly in ALS [27]. ...
Magnetic resonance spectroscopy (MRS) has contributed important academic insights in motor neuron diseases (MNDs), particularly in amyotrophic lateral sclerosis (ALS). Over the past three decades momentous methodological advances took place, including the emergence of high-field magnetic resonance imaging (MRI) platforms, multi-voxel techniques, whole-brain protocols, novel head-coil designs, and a multitude of open-source imaging suites. Technological advances in MRS are complemented by important conceptual developments in MND, such as the recognition of the importance of extra-motor brain regions, multi-timepoint longitudinal study designs, assessment of asymptomatic mutation carriers, description of genotype-associated signatures, and the gradual characterisation of non-ALS MND phenotypes. We have conducted a systematic review of published MRS studies in MND to identify important emerging research trends, key lessons from pioneering studies, and stereotyped shortcomings. We also sought to highlight notable gaps in the current literature so that research priorities for future studies can be outlined. While MRS remains relatively underutilised in MND compared to other structural, diffusivity and functional imaging modalities, our review suggests that MRS can not only advance our academic understanding of MND biology, but has a multitude of practical benefits for clinical and pharmaceutical trial applications.
... The reported cases of frank FTD evolved several years after the insidious onset of UMN signs and were associated with progressive radiological frontotemporal atrophy (91). This is in line with the mounting body of neuroimaging evidence that supports widespread frontotemporal involvement in PLS (22,29,33). ...
... The radiological profile of PLS varies from limited extramotor involvement to widespread pathology (27). Structural and diffusion data revealed degenerative changes in the fornix, body of the corpus callosum, anterior cingulate, dorsolateral prefrontal, insular, opercular, orbitofrontal, and temporal regions (22,27,29,33,37,42). Some studies have explored associations with underlying structural abnormalities focusing on apathy, impaired executive function, language, and verbal fluency deficits (29,33,92). ...
... Structural and diffusion data revealed degenerative changes in the fornix, body of the corpus callosum, anterior cingulate, dorsolateral prefrontal, insular, opercular, orbitofrontal, and temporal regions (22,27,29,33,37,42). Some studies have explored associations with underlying structural abnormalities focusing on apathy, impaired executive function, language, and verbal fluency deficits (29,33,92). Longitudinal studies have yielded inconsistent findings with regards to progressive pathology (25,26,(30)(31)(32)35). ...
Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.
... The core imaging signature of PLS is associated with motor cortex [11,70], corpus callosum [49] and CST degeneration. [71][72][73] More recently, brainstem [41,74], subcortical grey matter alterations [44,75], extra-motor cortical changes [11,40,93], and cerebellar degeneration [11] have also been reported. The majority of imaging studies in PLS are either MRI or PET studies r e v u e n e u r o l o g i q u e x x x ( 2 0 2 1 ) x x x -x x x [94], but a multimodal PET-MRI study can also be identified [95]. ...
Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can be challenging and therapeutic options are currently limited. There have been no recent clinical trials of disease-modifying therapies dedicated to this patient cohort and awareness of recent research developments is limited. The recent consensus diagnostic criteria introduced the category ‘probable’ PLS which is likely to curtail the diagnostic journey of patients. Extra-motor clinical manifestations are increasingly recognised, challenging the view of PLS as a 'pure' upper motor neuron condition. The post mortem literature of PLS has been expanded by seminal TDP-43 reports and recent PLS studies increasingly avail of meticulous genetic profiling. Research in PLS has gained unprecedented momentum in recent years generating novel academic insights, which may have important clinical ramifications.
... Cognitively, poor performance on tasks of attention and executive function have been associated with volume reductions in the dorsolateral prefrontal cortex and inferior frontal cortex . Specific associations of regional volume reduction with domain-specific cognitive impairment are inconsistent, usually due to the inclusion/stratification of cognitively heterogenous MND samples (Bede & Hardiman, 2014;Meoded et al., 2013;Mioshi et al., 2013;Schuster et al., 2014). Conversely, demonstrated cerebral grey matter changes in MND patients without cognitive and perceptual impairment Tsermentseli et al., 2012) suggest grey matter abnormalities may precede cognitive changes, a finding consistent with demonstrated structural changes in pre-symptomatic FTD C9orf72 carriers 5-10 years before expected symptom presentation . ...
... Conversely, demonstrated cerebral grey matter changes in MND patients without cognitive and perceptual impairment Tsermentseli et al., 2012) suggest grey matter abnormalities may precede cognitive changes, a finding consistent with demonstrated structural changes in pre-symptomatic FTD C9orf72 carriers 5-10 years before expected symptom presentation . White matter changes have also been identified in people with MND without overt cognitive impairment (Abe et al., 2004;Ciccarelli et al., 2009;Masuda et al., 2016;Sage et al., 2009;Thivard et al., 2007) and those with variable involvement of cognition and/or neuropsychiatric behaviour (Agosta et al., 2016;Meoded et al., 2013;Pettit et al., 2013;Sarro et al., 2011;Tsujimoto et al., 2011), where patients have been stratified into the same group if they have either cognitive or behavioural involvement. Significant correlations of diffusion tensor imaging (DTI) properties with cognition have mainly been identified for executive tasks. ...
Psychosis is a challenging feature of the syndromes of motor neurone disease (MND), frontotemporal dementia (FTD) and their overlap (FTD-MND). Clinically evident psychosis is not common, except in those with C9orf72+ expansions. However, subthreshold psychosis or pre-psychosis processes are common and provide the opportunity to study the mechanisms of psychosis in MND and FTD-MND. My aim was to identify the prevalence and the cognitive and neural correlates of psychosis, and related processes, in MND. I used a tiered cohort study approach. Tier 1 introduced screening as standard in a regional MND clinic (N=111) using the Edinburgh Cognitive and Behavioural ALS Screen and Cambridge Behavioural Inventory-Revised (CBI-R). In Tier 2, 60 patients and 30 controls underwent neuropsychological assessment, including (i) evidence-based decision-making, to quantify jumping to conclusions (JTC), (ii) attentional control and associative learning, (iii) perceptual inference, and (iv) psychiatric screening with Neuropsychiatric Inventory (NPI), Brief Psychiatric Rating Scale (BRPS), and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Tier 3 included magnetic resonance imaging of 30 patients and 20 controls. Carer reports in Tier 1 indicated that 10% of patients exhibited features suggestive of psychosis and 40% exhibited behavioural change. In Tier 2, many patients manifested abnormal behaviours (CBI-R 41%; NPI showed 19%; BPRS 24%), with 12-16% showing psychosis-specific symptoms (CBI-R and NPI psychosis index scores). In the jumping to conclusions task, patients made decisions based on less evidence than controls and were insensitive to negative feedback. Carer ratings of patient behaviour correlated with performance on the jumping to conclusions task when decisions were rewarded or costs fixed. Attentional shifting and perceptual inference were normal in MND. A principal component analysis (PCA) of questionnaires revealed two component scores, reflecting distinct patients’ and carers’ perspectives. The imaging analyses focused on the correlates of jumping to conclusions and insensitivity to negative feedback, as a potential risk profile for psychosis, with exploratory analyses of the correlates of the CBI-R psychosis index, and carers’ ratings of behaviour from the PCA. Using a Freesurfer regions-of-interest approach, grey matter volume correlated inversely with CBI-R psychosis index in the caudate, amygdala, cingulate and hippocampus. Using tract-based spatial statistics, increased mean diffusivity (MD) of diffusion weighted imaging correlated with the CBI-R psychosis responses in inferior longitudinal and uncinate fasciculi. Cost sensitivity in the JTC task correlated with cingulate and cerebellar grey matter volumes. White matter correlates of cost sensitivity included reduced FA with increasing cost sensitivity in white matter connecting the inferior frontal lobe in controls and patients. Although overt psychosis is uncommon in MND, many patients displayed abnormal behaviour or cognitive symptoms, including suboptimal reasoning biases and inferential impulsivity. Degeneration of cerebellar, cingulate and striatal grey matter, and adjacent major white matter tracts, may underlie these cognitive impairments and together represent a vulnerability to develop psychosis. Compromised reasoning and inference have implications for clinical management, including decisions around treatment options and management of well-being in MND.
... Long disease duration of PLS may not be the only explanation for the prominent cortical atrophy because it is unusual to observe in even advanced longstanding cases of ALS. Furthermore, significant atrophy in PLS, including underlying white matter, has also been noted to extend more anteriorly (21,22), with MRI changes sometimes linked to cognitive impairment (23,24). ...
... Over 20 diffusion tensor imaging studies have been published in PLS which consistently capture CST pathology (30-32), but cerebellar (9,48), and corpus callosum (37,49) pathologies have also been described. Some studies have specifically highlighted extra-motor, extra-corpus callosum diffusivity alterations involving the superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes (23,24). ...
Increased interest in the underlying pathogenesis of primary lateral sclerosis (PLS) and its relationship to amyotrophic lateral sclerosis (ALS) has corresponded to a growing number of CNS imaging studies, especially in the past decade. Both its rarity and uncertainty of definite diagnosis prior to 4 years from symptom onset have resulted in PLS being less studied than ALS. In this review, we highlight most relevant papers applying magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) to analyzing CNS changes in PLS, often in relation to ALS. In patients with PLS, mostly brain, but also spinal cord has been evaluated since significant neurodegeneration is essentially restricted to upper motor neuron (UMN) structures and related pathways. Abnormalities of cortex and subcortical white matter tracts have been identified by structural and functional MRI and MRS studies, while metabolic and cell-specific changes in PLS brain have been revealed using various PET radiotracers. Future neuroimaging studies will continue to explore the interface between the PLS-ALS continuum, identify more changes unique to PLS, apply novel MRI and MRS sequences showing greater structural and neurochemical detail, as well as expand the repertoire of PET radiotracers that reveal various cellular pathologies. Neuroimaging has the potential to play an important role in the evaluation of novel therapies for patients with PLS.
... From a radiological perspective PLS is classically associated with motor cortex atrophy [2,59,91], corpus callosum [92,93] and corticospinal tract degeneration [94][95][96], but more recently, brainstem [97], temporal lobe [59], cerebellar [59] and subcortical grey matter changes have also been described [17,18]. Consistent with the expanding literature of extramotor changes in PLS white matter alterations have been described in the superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes based on diffusivity metrics [98,99]. Emerging evidence of neuropsychological deficits [87,88] provide the rational for the targeted assessment of temporal lobe changes in PLS. ...
Temporal lobe studies in motor neuron disease overwhelmingly focus on white matter alterations and cortical grey matter atrophy. Reports on amygdala involvement are conflicting and the amygdala is invariably evaluated as a single structure despite consisting of several functionally and cytologically distinct nuclei. A prospective, single-centre, neuroimaging study was carried out to comprehensively characterise amygdala pathology in 100 genetically-stratified ALS patients, 33 patients with PLS and 117 healthy controls. The amygdala was segmented into groups of nuclei using a Bayesian parcellation algorithm based on a probabilistic atlas and shape deformations were additionally assessed by vertex analyses. The accessory basal nucleus (p = .021) and the cortical nucleus (p = .022) showed significant volume reductions in C9orf72 negative ALS patients compared to controls. The lateral nucleus (p = .043) and the cortico-amygdaloid transition (p = .024) were preferentially affected in C9orf72 hexanucleotide carriers. A trend of total volume reduction was identified in C9orf72 positive ALS patients (p = .055) which was also captured in inferior-medial shape deformations on vertex analyses. Our findings highlight that the amygdala is affected in ALS and our study demonstrates the selective involvement of specific nuclei as opposed to global atrophy. The genotype-specific patterns of amygdala involvement identified by this study are consistent with the growing literature of extra-motor clinical features. Mesial temporal lobe pathology in ALS is not limited to hippocampal pathology but, as a key hub of the limbic system, the amygdala is also affected in ALS.
https://doi.org/10.1016/j.jns.2020.117039
