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Representative examples of diffuse cortical atrophy in MRI scans of ALS patients with C9orf72 mutations. The demographic information and scores on motor and cognitive scales are listed below each patient's scan. (A) Compared to age-matched controls, mild ventricular enlargement was seen in C9+ patients 1, 2, and 3 who had ALS, but good cognitive function, as evidenced by their scores on the Mattis Dementia Rating Scale−2 (DRS-2). The surface rendering of one patient [left side of panel (A)] shows sulci in frontal lobe sulci are also mildly enlarged compared to the occipital lobe. (B) C9+ patients 4, 5, and 6 had ALS-FTD with a similar degree of motor dysfunction to those in panel (A), as measured by their ALS functional rating scale revised (ALSFRS-R) scores, but marked cognitive impairment with low DRS-2 scores. There is marked enlargement of ventricles evident in axial slices, as well as enlargement of frontal and temporal sulci in the surface rendering at left of panel (B).
Source publication
Now that genetic testing can identify persons at risk for developing amyotrophic lateral sclerosis (ALS) many decades before symptoms begin, there is a critical need for biomarkers that signal the onset and progression of degeneration. The search for candidate disease biomarkers in patients with mutations in the gene C9orf72 has included imaging, p...
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Citations
... Attempts to discover fluid-based ALS biomarkers have been accomplished chiefly using CSF due to its close position to the neuroanatomical region affected by the disease. However, recent findings have also studied serum and plasma, and scientists' attempt to conduct studies based on urine and saliva is emerging [10,19]. For instance, cystatin C, detected in the CSF samples of ALS patients, also known as a cysteine protease inhibitor is conceptualized to participate in the procedures resulting in the formation of the Bunina bodies in the intraneuronal areas [10]. ...
... Two main EV types have been described as exosomes and microvesicles (MVs). MVs of ALS patients have been identified to be enriched by the accumulation of ALS-related proteins, namely SOD1, TDP-43, pTDP-43, and FUS [16], suggesting EV-mediated prionlike propagation of ALS disease [19], these mutant proteins retrieved in EVs are delivered across the brain cells and spread the disease (Table 1). In addition, the Chen et al. 2020 results investigating TDP-43, NFL, and pNFL in the exosomes derived from plasma samples reported an enhancement of TDP-43 and NFL in exosomes of the ALS group, over time highlighted its prognostic role [24]. ...
Background
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Due to the limited knowledge about potential biomarkers that help in early diagnosis and monitoring disease progression, today’s diagnoses are based on ruling out other diseases, neurography, and electromyography examination, which takes a time-consuming procedure.
Methods
PubMed, ScienceDirect, and Web of Science were explored to extract articles published from January 2015 to June 2023. In the searching strategy following keywords were included; amyotrophic lateral sclerosis, biomarkers, cerebrospinal fluid, serum, and plama.
Results
A total number of 6 studies describing fluid-based exosomal biomarkers were included in this study. Aggregated proteins including SOD1, TDP-43, pTDP-43, and FUS could be detected in the microvesicles (MVs). Moreover, TDP-43 and NFL extracted from plasma exosomes could be used as prognostic biomarkers. Also, downregulated miR-27a-3p detected through exoEasy Maxi and exoQuick Kit in the plasma could be measured as a diagnostic biomarker. Eventually, the upregulated level of CORO1A could be used to monitor disease progression.
Conclusion
Based on the results, each biomarker alone is insufficient to evaluate ALS. CNS-derived exosomes contain multiple ALS-related biomarkers (SOD1, TDP-43, pTDP-43, FUS, and miRNAs) that are detectable in cerebrospinal fluid and blood is a proper alternation. Exosome detecting kits listed as exoEasy, ExoQuick, Exo-spin, ME kit, ExoQuick Plus, and Exo-Flow, are helpful to reach this purpose.
... Beraz, SOD1 bezala, FUS ere TDP-43tik independentea da [12]. [11,20,32]. NF-L kateen kontzentrazio serikoek % 90tik gorako sentsibilitatea eta espezifikotasuna dute AEA duten pazienteak kontrol osasuntsuetatik bereizteko [13] ...
Alboko esklerosi amiotrofikoa (AEA) gaixotasun neurodegeneratibo heterogeneo eta sendaezina da. Goiko eta beheko neurona motorren endekapena eta bizkarmuineko alboko kordoiaren esklerosia dira zigilu histopatologiko nagusiak. Adierazpen klinikoetan aldakortasun handia dagoen arren, ahultasun orokorra, faszikulazioak eta espasmoak gertatzen dira neurona motorren endekapenaren eta muskulu-atrofiaren ondorioz, eta baita portaera- eta kognizio-asaldurak ere garuneko kalte zabala dela eta. Mutazio genetikoek gaixotasunaren bi adierazpen nagusietan (AEA esporadikoa eta familiako AEA) eragiten dute. Identifikatu diren gene inplikatuen artean, C9orf72, SOD1, TARDBP eta FUS dira nagusienak, baina gene horiek AEA esporadikoaren kasuen % 15 eta familiako AEA kasuen % 66 baino ez dituzte azaltzen. Egungo tratamenduek sintomatologia moteltzea dute helburu eta dauden terapia farmakologikoak urriak eta eraginkortasun txikikoak dira, gehienbat, diagnostikoa beranduegi egiten delako. Izan ere, AEA diagnostikatzeko eta gaixotasunaren larritasuna jarraitzeko erabiltzen diren eskalak sintomen eta zeinuen balorazioan oinarritzen dira, eta horiek kalte neuronala dagoeneko gertatu denean adierazten dira. Hortaz, premiazkoa da AEAren diagnostiko goiztiarrerako biomarkatzaile espezifiko eta fidagarriak aurkitzea. Orain arte, fluido biologikoetan gehien aztertu diren eta emaitzarik sendoenak eman dituzten biomarkatzaileak C9orf72 genetik eratorritako proteinak, TDP-43 proteinaren aldaerak eta neurofiruen azpiunitateak dira. Hala ere, hainbat ikerlanek hanturaren markatzaileak eta markatzaile metabolikoen garrantzia ere azpimarratu dute AEAren diagnostiko-biomarkatzaile gisa. Dena den, oraindik ez da aurkitu behin betiko biomarkatzailerik AEA estratifikatzeko, beste entitate nosologiko batzuetatik bereizteko eta gaixotasunaren jarraipena egiteko, eta ebidentziek biomarkatzaileen konbinazioak beharko direla erakusten dute. Nolanahi ere, biomarkatzaile berriak aurkitzeko, ikerketa gehiago egin behar da gaixotasuna bera ulertzeko; izan ere, AEA interakzio-mekanismo ugariren emaitza da eta urrun gaude etiopatogenia eta fisiopatologia bere osotasunean ulertzetik
... Higher levels of NfL and p-NfH in blood and CSF were reported in ALS patients with C9orf72 mutations as compared to ALS patients with SOD1 mutations or without any known causative genetic mutation (Wiesenfarth et al. 2023;Benatar et al., 2020). Neuroimaging is another promising in vivo biomarker, particularly structural MRI to measure gray matter atrophy and diffusion tensor imaging (DTI) to assess alterations in structural white matter connectivity (Feldman et al., 2022;Floeter and Gendron, 2018). In ALS patients with C9orf72 mutations, significant differences in structural MRI have been reported compared to ALS patients without these hexanucleotide expansions, especially in extramotor regions such as cortical and subcortical frontotemporal areas as well as the thalamus (Byrne et al., 2012;Floeter and Gendron, 2018;Bede et al., 2013;Agosta et al., 2017). ...
... Neuroimaging is another promising in vivo biomarker, particularly structural MRI to measure gray matter atrophy and diffusion tensor imaging (DTI) to assess alterations in structural white matter connectivity (Feldman et al., 2022;Floeter and Gendron, 2018). In ALS patients with C9orf72 mutations, significant differences in structural MRI have been reported compared to ALS patients without these hexanucleotide expansions, especially in extramotor regions such as cortical and subcortical frontotemporal areas as well as the thalamus (Byrne et al., 2012;Floeter and Gendron, 2018;Bede et al., 2013;Agosta et al., 2017). Westeneng et al. reported widespread cortical alterations , and Agosta et al. described especially cerebellar and thalamic damage as well as occipital cortical thinning as findings in MRI of ALS patients with C9orf72 mutations (Agosta et al., 2017). ...
... There are previous MRI based studies discussing the question of a characteristic MRI signature of ALS patients with C9orf72 mutations, in part with heterogeneous results (Agosta et al., 2017;Bede et al., 2018;Chipika et al., 2020;Floeter and Gendron, 2018;Häkkinen et al., 2020;Li Hi Shing et al., 2021;Omer et al., 2017;van der Burgh et al., 2020;Westeneng et al., 2016). Westeneng et al. (n = 14) reported cortical atrophy in the opercular, fusiform, lingual, isthmus-cingulate and superior parietal cortex to be typical for these patients . ...
Background:
ALS patients with hexanucleotide expansion in C9orf72 are characterized by a specific clinical phenotype, including more aggressive disease course and cognitive decline. Computerized multiparametric MRI with gray matter volumetry and diffusion tensor imaging (DTI) to analyze white matter structural connectivity is a potential in vivo biomarker.
Objective:
The objective of this study was to develop a multiparametric MRI signature in a large cohort of ALS patients with C9orf72 mutations. The aim was to investigate how morphological features of C9orf72-associated ALS differ in structural MRI and DTI compared to healthy controls and ALS patients without C9orf72 mutations.
Methods:
Atlas-based volumetry (ABV) and whole brain-based DTI-based analyses were performed in a cohort of n = 51 ALS patients with C9orf72 mutations and compared with both n = 51 matched healthy controls and n = 51 C9orf72 negative ALS patients, respectively. Subsequently, Spearman correlation analysis of C9orf72 ALS patients' data with clinical parameters (age of onset, sex, ALS-FRS-R, progression rate, survival) as well as ECAS and p-NfH in CSF was performed.
Results:
The whole brain voxel-by-voxel comparison of fractional anisotropy (FA) maps between C9orf72 ALS patients and controls showed significant bilateral alterations in axonal structures of the white matter at group level, primarily along the corticospinal tracts and in fibers projecting to the frontal lobes. For the frontal lobes, these alterations were also significant between C9orf72 positive and C9orf72 negative ALS patients. In ABV, patients with C9orf72 mutations showed lower volumes of the frontal, temporal, and parietal lobe, with the lowest values in the gray matter of the superior frontal and the precentral gyrus, but also in hippocampi and amygdala. Compared to C9orf72 negative ALS, the differences were shown to be significant for cerebral gray matter (p = 0.04), especially in the frontal (p = 0.01) and parietal lobe (p = 0.01), and in the thalamus (p = 0.004). A correlation analysis between ECAS and averaged regional FA values revealed significant correlations between cognitive performance in ECAS and frontal association fibers. Lower FA values in the frontal lobes were associated with worse performance in all cognitive domains measured (language, verbal fluency, executive functions, memory and spatial perception). In addition, there were significant negative correlations between age of onset and atlas-based volumetry results for gray matter.
Conclusions:
This study demonstrates a distinct pattern of DTI alterations of the white matter and ubiquitous volume reductions of the gray matter early in the disease course of C9orf72-associated ALS. Alterations were closely linked to a more aggressive cognitive phenotype. These results are in line with an expected pTDP43 propagation pattern of cortical affection and thus strengthen the hypothesis that an underlying developmental disorder is present in ALS with C9orf72 expansions. Thus, multiparametric MRI could contribute to the assessment of the disease as an in vivo biomarker even in the early phase of the disease.
... Nijboer and previously other authors reported posterior cortical atrophy in some phenotype of ALS patients, thought conventional and post-processing MRI images. This pathological finding has been observed in Alzheimer disease too [41][42][43][44]. In our patients, posterior areas were very affected, it was demonstrated by different techniques. ...
... They showed cortical thickness was not significantly different between ALS patients and healthy controls (p=0.258) [42] . Meyer and other authors have done post-mortem and MRI studies and they have shown approximately 1.5 times greater cortical thickness of the precentral compared to the postcentral cortex in ALS patients [43][44][45] . ...
... It is well-known that ALS is a heterogeneous disease in its initial clinical manifestations, as well as in its evolutionary progression [10]. Recently, numerous epidemiological (age of onset, sex), genetic and biological poor prognostic factors have been described [4,[11][12][13]. In the present study, we have tried to evaluate CSF protein, albumin, and QAlb index elevation as poor prognostic factors. ...
Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease, both in its onset phenotype and in its rate of progression. The aim of this study was to establish whether the dysfunction of the blood–brain barrier (BBB) and blood–spinal cord barrier (BSCB) measured through cerebrospinal fluid (CSF) proteins and the albumin-quotient (QAlb) are related to the speed of disease progression. An amount of 246 patients diagnosed with ALS were included. CSF and serum samples were determined biochemically for different parameters. Survival analysis based on phenotype shows higher probability of death for bulbar phenotype compared to spinal phenotype (p-value: 0.0006). For the effect of CSF proteins, data shows an increased risk of death for spinal ALS patients as the value of CSF proteins increases. The same model replicated for CSF albumin yielded similar results. Statistical models determined that the lowest cut-off value for CSF proteins able to differentiate patients with a good prognosis and worse prognosis corresponds to CSF proteins � 0.5 g/L (p-value: 0.0189). For the CSF albumin, the QAlb �0.65 is associated with elevated probability of death (p-value: 0.0073). High levels of QAlb are a bad prognostic indicator for the spinal phenotype, in addition to high CSF proteins levels that also act as a marker of poor prognosis.
... The field of genetic ALS continues to develop rapidly with multiple disease gene discoveries per year (128), with the autosomal dominant inheritance of a hexanucleotide expansion in the first intron of the C9orf72 gene being the most common cause of familial ALS in people of Northern European ancestry, also as a major contributor to frontotemporal pathology in ALS. DTI studies in patients with C9orf72 expansion in crosssectional and longitudinal design demonstrated alterations in motor tracts (129)(130)(131); in addition, further white matter areas were found to be affected, e.g., in the frontal white matter (132) and segmentally in the corpus callosum (133). In addition, the in vivo histopathological staging approach was also applied to C9orf72-associated ALS and demonstrated a corticoefferent involvement pattern according to the staging scheme-a pattern that was not observed in Super Oxide Dismutase 1-associated ALS (134). ...
... Current initiatives have, thus, integrated natural history and biomarker data on presymptomatic ALS for the design and implementation of pre-symptomatic ALS trials (136). Specifically, in C9orf72 mutation carriers, DTI studies reported regional reductions of white matter integrity (131,137), as an indicator of general developmental tardiness. At the spinal level, C9orf72-positive subjects older than 40 years were shown to exhibit considerable WM atrophy at C2-C7 vertebral levels in conjunction with progressive pyramidal tract FA reductions (138). ...
Neuroimaging assessment of motor neuron disease has turned into a cornerstone of its clinical workup. Amyotrophic lateral sclerosis (ALS), as a paradigmatic motor neuron disease, has been extensively studied by advanced neuroimaging methods, including molecular imaging by MRI and PET, furthering finer and more specific details of the cascade of ALS neurodegeneration and symptoms, facilitated by multicentric studies implementing novel methodologies. With an increase in multimodal neuroimaging data on ALS and an exponential improvement in neuroimaging technology, the need for harmonization of protocols and integration of their respective findings into a consistent model becomes mandatory. Integration of multimodal data into a model of a continuing cascade of functional loss also calls for the best attempt to correlate the different molecular imaging measurements as performed at the shortest inter-modality time intervals possible. As outlined in this perspective article, simultaneous PET/MRI, nowadays available at many neuroimaging research sites, offers the perspective of a one-stop shop for reproducible imaging biomarkers on neuronal damage and has the potential to become the new gold standard for characterizing motor neuron disease from the clinico-radiological and neuroscientific perspectives.
... Motor Neuron Diseases (MNDs) are a heterogeneous group of neurodegenerative conditions with divergent disability profiles [1], survival characteristics [2] and pathological patterns [3,4]. Imaging studies in MNDs are dominated by structural [5,6], diffusion [7] and fMRI studies [8,9], despite landmark magnetic resonance spectroscopy (MRS) studies, confirming medication effects [10], detecting presymptomatic changes [11], describing alterations in cortical [12] and subcortical [13] regions, in cross-sectional and longitudinal studies [14,15]. ...
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.
... Volumetric MRI has also pointed out the presence of basal ganglia nuclei atrophy as well as of the corpus callosum [45,54]. ...
The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.
... Finally, the lack of comprehensive genetic evaluation is a shortcoming of our report. GGGGCC hexanucleotide repeat expansions have been associated with marked frontotemporal involvement in ALS (Floeter and Gendron 2018;Floeter et al. 2016;Bede et al. 2013), but extra-motor degeneration is not unique to this genotype (Westeneng et al. 2016). ...
Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD) may present typical behavioral variant FTD symptoms. This study aims to determine whether profile and severity of cognitive-behavioral symptoms in ALS/ALS-FTD are predicted by regional cortical atrophy. The hypothesis is that executive dysfunction can be predicted by dorsolateral prefrontal cortical (dlPFC) atrophy, apathy by dorsomedial PFC (dmPFC) and anterior cingulate cortical (ACC) atrophy, disinhibition by orbitofrontal cortical (OFC) atrophy. 3.0 Tesla MRI scans were acquired from 22 people with ALS or ALS-FTD. Quantitative cortical thickness analysis was performed with FreeSurfer. A priori-defined regions of interest (ROI) were used to measure cortical thickness in each participant and calculate magnitude of atrophy in comparison to 115 healthy controls. Spearman correlations were used to evaluate associations between frontal ROI cortical thickness and cognitive-behavioral symptoms, measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinical Dementia Rating (CDR) scale. ALS-FTD participants exhibited variable degrees of apathy (NPI-Q/apathy: 1.6 ± 1.2), disinhibition (NPI-Q/disinhibition: 1.2 ± 1.2), executive dysfunction (CDR/judgment-problem solving: 1.7 ± 0.8). Within the ALS-FTD group, executive dysfunction correlated with dlPFC atrophy (ρ:-0.65;p < 0.05); similar trends were seen for apathy with ACC (ρ:-0.53;p < 0.10) and dmPFC (ρ:-0.47;p < 0.10) atrophy, for disinhibition with OFC atrophy (ρ:-0.51;p < 0.10). Compared to people with ALS, those with ALS-FTD showed more diffuse atrophy involving precentral gyrus, prefrontal, temporal regions. Profile and severity of cognitive-behavioral symptoms in ALS-FTD are predicted by regional prefrontal atrophy. These findings are consistent with established brain-behavior models and support the role of quantitative MRI in diagnosis, management, counseling, monitoring and prognostication for a neurodegenerative disorder with diverse phenotypes.
