Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis

Gregory, Jenna M; Elliott, Elizabeth; McDade, Karina; Bak, Thomas H.; Pal, Suvankar; Chandran, Siddharthan; Abrahams, Sharon; Smith, Colin

doi:10.1111/nan.12575

Cited by 20 publications

(27 citation statements)

References 25 publications

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“…Therefore, in every case exhibiting ALSci, there was evidence of extramotor TDP-43 pathology. There were six false negatives, whereby TDP-43 pathology in extramotor brain regions was not accompanied by an impairment in the ECAS 24. These data taken together were used to assess the diagnostic accuracy of ECAS in predicting TDP-43 pathology in extramotor brain regions resulting in a diagnostic accuracy of 66.67% (95% CI 46.04 to 83.48), with a sensitivity of 43.75% (95% CI 19.75 to 70.12) and a specificity of 100% (95% CI 71.51 to 100).…”

Section: Resultsmentioning

confidence: 95%

“…However, the major limitation to this is the lower sensitivity of the ECAS in predicting this burden of pathology, meaning that some patients, who could plausibly benefit from such a trial, would not be identified. However, recently we identified a striking difference in spatial expression of a pathological marker called clusterin in mismatch cases that would not be identified by the ECAS 24. It is therefore plausible that biomarkers exist that could be developed to enable improved sensitivity to identify further individuals that may be missed by the ECAS testing.…”

Section: Discussionmentioning

confidence: 99%

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Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS

Gregory

McDade

Bak

et al. 2019

J Neurol Neurosurg Psychiatry

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ObjectiveApproximately 35% of patients with amyotrophic lateral sclerosis (ALS) exhibit mild cognitive deficits in executive functions, language and fluency, without dementia. The precise pathology of these extramotor symptoms has remained unknown. This study aimed to determine the pathological correlate of cognitive impairment in patients with non-demented ALS.MethodsIn-depth neuropathological analysis of 27 patients with non-demented ALS who had undergone cognitive testing (Edinburgh Cognitive and Behaviour ALS Screen (ECAS)) during life. Analysis involved assessing 43 kDa Tar-DNA binding protein (TDP-43) accumulation in brain regions specifically involved in executive functions, language functions and verbal fluency to ascertain whether functional deficits would relate to a specific regional distribution of pathology.ResultsAll patients with cognitive impairment had TDP-43 pathology in extramotor brain regions (positive predictive value of 100%). The ECAS also predicted TDP-43 pathology with 100% specificity in brain regions associated with executive, language and fluency domains. We also detected a subgroup with no cognitive dysfunction, despite having substantial TDP-43 pathology, so called mismatch cases.ConclusionsCognitive impairment as detected by the ECAS is a valid predictor of TDP-43 pathology in non-demented ALS. The profile of mild cognitive deficits specifically predicts regional cerebral involvement. These findings highlight the utility of the ECAS in accurately assessing the pathological burden of disease.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS

Gregory

McDade

Bak

et al. 2019

J Neurol Neurosurg Psychiatry

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“…To this end, research is underway to improve our understanding of the molecular mechanisms underlying ALS. This may in turn reveal potential important therapeutic targets, including those that modulate cognition [ 27 , 28 ]. Cognitive assessments have been included in some studies investigating the effects of rilzuole as a disease modifying therapy in various other neurodegenerative conditions [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

A systematic review of neuropsychiatric and cognitive assessments used in clinical trials for amyotrophic lateral sclerosis

et al. 2020

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Background Up to 50% of people with amyotrophic lateral sclerosis (ALS) experience cognitive dysfunction, whilst depression and anxiety are reported in up to 44% and 33%, respectively. These symptoms impact on quality of life, and are associated with a poorer prognosis. Historically, outcomes in clinical trials have focused on the effect of candidate drugs on physical functioning. Methods We reviewed the past 25 years of clinical trials of investigative medicinal products in people with ALS, since the licensing of riluzole, and extracted data on frequency and type of assessment for neuropsychiatric symptoms and cognitive impairment. Trial registry databases, including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed, were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 31/10/2019. No language restrictions were applied. Outcome measures, exclusion criteria and assessment tool used were extracted. Results 216 trials, investigating 26,326 people with ALS, were reviewed. 35% assessed neuropsychiatric symptoms, and 22% assessed cognition, as Exclusion Criteria or Outcome Measures. 3% (n = 6) of trials assessed neuropsychiatric symptoms as a Secondary Outcome Measure, and 4% (n = 8) assessed cognition as Outcome Measures; only one trial included assessments for both cognition and neuropsychiatric symptoms as Outcome Measures. Three ALS-specific assessments were used in six trials. Conclusions Trials for people with ALS have neglected the importance of neuropsychiatric symptoms and cognitive impairment. Evaluation of these extra-motor features is essential to understanding the impact of candidate drugs on all symptoms of ALS. PROPSERO registration CRD42020175612.

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“…Aside from a possible regional specialisation shown by prefrontal and parietal tracts, the association might have in part emerged as the result of a certain vulnerability observed in these regions. Prefrontal and parietal deposition of TDP-43 pathology, in fact, is detectable in ALS patients regardless of cognitive impairment [38], indicating that pathological changes in these regions are not uncommon in ALS regardless of speech difficulties.…”

Section: Discussionmentioning

confidence: 94%

Right fronto-parietal white matter disruption contributes to speech impairments in amyotrophic lateral sclerosis

Merico

Marco

Berta

et al. 2020

Brain Research Bulletin

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Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis

Cited by 20 publications

References 25 publications

Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS

Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS

A systematic review of neuropsychiatric and cognitive assessments used in clinical trials for amyotrophic lateral sclerosis

Right fronto-parietal white matter disruption contributes to speech impairments in amyotrophic lateral sclerosis

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