Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants

Borrego‐Écija, Sergi; Turón-Sans, Janina; Ximelis, Teresa; Aldecoa, Ibán; Molina‐Porcel, Laura; Povedano, Mònica; Rubio, Miguel A.; Gámez, Josep; Cano, Antonio; Paré-Curell, M.; Bajo, Lorena; Sotoca, Javier; Clarimón, Jordi; Balasa, Mircea; Antonell, Anna; Lladó, Albert; Sánchez‐Valle, Raquel; Rojas‐García, Ricard; Gelpí, Ellen

doi:10.1111/bpa.12942

Cited by 18 publications

(15 citation statements)

References 49 publications

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“…Frontotemporal lobar degeneration explains cognitive impairment only in some ALS patients, while other features such as the extent of TDP-43 pathology and the presence of hippocampal sclerosis may also contribute to cognitive disturbances [ 33 ]. Neuroimaging studies have shown the involvement of extra-motor brain regions such as the hypothalamus [ 34 ], frontotemporal areas, cerebellum, and basal ganglia [ 35 , 36 , 37 , 38 ].…”

Section: Non-motor and Non-sensory Alterations In Alsmentioning

confidence: 99%

Sensory Involvement in Amyotrophic Lateral Sclerosis

Rubio

Herrando-Grabulosa

Navarro

2022

IJMS

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Although amyotrophic lateral sclerosis (ALS) is pre-eminently a motor disease, the existence of non-motor manifestations, including sensory involvement, has been described in the last few years. Although from a clinical perspective, sensory symptoms are overshadowed by their motor manifestations, this does not mean that their pathological significance is not relevant. In this review, we have made an extensive description of the involvement of sensory and autonomic systems described to date in ALS, from clinical, neurophysiological, neuroimaging, neuropathological, functional, and molecular perspectives.

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Section: Non-motor and Non-sensory Alterations In Alsmentioning

confidence: 99%

Sensory Involvement in Amyotrophic Lateral Sclerosis

Rubio

Herrando-Grabulosa

Navarro

2022

IJMS

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“…When studied with specifically designed instruments, such as the Edinburgh ALS cognitive and behavioral screen (ECAS), the ALS cognitive behavioral screen, or the Arrows and Colors Cognitive Test, up to 20% of patients with ALS can also be diagnosed with FTD, and up to 50% of patients with ALS have a cognitive or behavioral impairment (ALScbi) ( 6 , 10 , 32 – 36 ). The frequency and characteristics of cognitive and behavioral impairment resemble those noted in FTD, and recent neuropathological studies have reported frontotemporal involvement consistent with the diagnosis of FTLD in more than 30% of patients with ALS ( 37 ). Among the most common cognitive symptoms developed in patients with ALS-FTD are executive dysfunction, language impairment, and social cognition, all of which are linked to the frontal and temporal lobes ( 6 , 33 ).…”

Section: Extra-motor Involvement In Alsmentioning

confidence: 77%

“…Notably, the degree of synapse loss correlated with the severity of the patients' cognitive impairment independent of cortical atrophy, supporting the idea that synapse loss precedes neuronal loss ( 109 , 110 ). Finally, Tau pathology and hippocampal sclerosis may also play a secondary role in the presence of cognitive impairment in patients with ALS ( 37 , 111 , 112 ).…”

Section: Extra-motor Involvement In Alsmentioning

confidence: 99%

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies

et al. 2022

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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.

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“…57 Cognitive dysfunction and extramotor atrophy in ALS was found to be influenced by a polygenic risk profile due to a range of genetic polymorphisms, 34 while cognitive decline in ALS patients was more likely to occur in those with more extensive TDP-43 deposition and additional neuropathological features typical of FTLD. 35 The emergence of cognitive phenotypes across the spectrum of amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) and more widespread TDP-43 deposition appears to depend on the expression of particular protein networks, in particular networks enriched with ribonucleic acid (RNA) binding proteins, and markers of microglial function also appear to drive phenotypic expression. 33 Several studies establish the association between expansions in C9orf72, ALS and frontotemporal dementia (FTD), strengthening the notion that these clinical phenotypes exist on a continuum, while also identifying the neuropathological hallmarks of this mutation, notably the presence of p62 positive inclusions and dipeptide repeat aggregates.…”

Section: Clinico-pathological Studiesmentioning

confidence: 99%

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review

Mazumder

Kiernan

Halliday

et al. 2022

Neuropathology Appl Neurobio

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Over the past decade, considerable efforts have been made to accelerate pathophysiological understanding of fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with brain banks at the forefront. In addition to exploratory disease mechanisms, brain banks have aided our understanding with regard to clinical diagnosis, genetics and cell biology. Across neurodegenerative disorders, the impact of brain tissue in ALS research has yet to be quantified. This review aims to outline (i) how postmortem tissues from brain banks have influenced our understanding of ALS over the last 15 years, (ii) correlate the location of dedicated brain banks with the geographical prevalence of ALS, (iii) identify the frequency of features reported from postmortem studies and (iv) propose common reporting standards for materials obtained from dedicated brain banks. A systematic review was conducted using PubMed and Web of Science databases using key words. From a total of 1439 articles, 73 articles were included in the final review, following PRISMA guidelines. Following a thematic analysis, articles were categorised into five themes; clinico‐pathological (13), genetic (20), transactive response DNA binding protein 43 (TDP‐43) pathology (12), non‐TDP‐43 neuronal pathology (nine) and extraneuronal pathology (19). Research primarily focused on the genetics of ALS, followed by protein pathology. About 63% of the brain banks were in the United States of America and United Kingdom. The location of brain banks overall aligned with the incidence of ALS worldwide with 88% of brain banks situated in Europe and North America. An overwhelming lack of consistency in reporting and replicability was observed, strengthening the need for a standardised reporting system. Overall, postmortem material from brain banks generated substantial new knowledge in areas of genetics and proteomics and supports their ongoing role as an important research tool.

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Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants

Cited by 18 publications

References 49 publications

Sensory Involvement in Amyotrophic Lateral Sclerosis

Sensory Involvement in Amyotrophic Lateral Sclerosis

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review

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