Thalamus: aspekti ALS

(1)  https://www.ncbi.nlm.nih.gov/pubmed/?term=ALS%2C+thalamus

Brain Pathol. 2018 Jan;28(1):14-27. doi: 10.1111/bpa.12467. Epub 2017 Mar 22.

Neurodegeneration and NLRP3 inflammasome expression in the anterior thalamus of SOD1(G93A) ALS mice.

Debye B¹, Schmülling L¹, Zhou L², Rune G², Beyer C¹, Johann S¹. Abstract

Nowadays, amyotrophic lateral sclerosis (ALS) is considered as a multisystem disorder, characterized by a primary degeneration of motor neurons as well as neuropathological changes in non-motor regions. Neurodegeneration in subcortical areas, such as the thalamus, are believed to contribute to cognitive and behavioral abnormalities in ALS patients. In the present study, we investigated neurodegenerative changes including neuronal loss and glia pathology in the anterodorsal thalamic nucleus (AD) of SOD1(G93A) mice, a widely used animal model for ALS. We detected massive dendrite swelling and neuronal loss in SOD1(G93A) animals, which was accompanied by a mild gliosis. Furthermore, misfolded SOD1 protein and autophagy markers were accumulating in the AD.
Since innate immunity and activation inflammasomes seem to play a crucial role in ALS, we examined protein expression of Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) and the cytokine interleukin 1 beta (IL1β) in AD glial cells and neurons. NLRP3 and ASC were significantly up-regulated in the AD of SOD1(G93A) mice. Finally, co-localization studies revealed expression of NLRP3, ASC and IL1β in neurons. Our study yielded two main findings: (i) neurodegenerative changes already occur at an early symptomatic stage in the AD and (ii) increased inflammasome expression may contribute to neuronal cell death. In conclusion, neurodegeneration in the anterior thalamus may critically account for cognitive changes in ALS pathology.

(2)

Front Aging Neurosci. 2018 Mar 15;10:45. doi: 10.3389/fnagi.2018.00045. eCollection 2018.

Atrophy in the Thalamus But Not Cerebellum Is Specific for C9orf72 FTD and ALS Patients - An Atlas-Based Volumetric MRI Study. Schönecker S¹, Neuhofer C¹, Otto M², Ludolph A², Kassubek J², Landwehrmeyer B², Anderl-Straub S², Semler E², Diehl-Schmid J³, Prix C¹, Vollmar C¹, Fortea J⁴; Deutsches FTLD-Konsortium, Huppertz HJ⁵, Arzberger T⁶, Edbauer D^7,8,9, Feddersen B¹⁰, Dieterich M^1,7,9, Schroeter ML^11,12, Volk AE¹³, Fließbach K^14,15, Schneider A^14,15, Kornhuber J¹⁶, Maler M¹⁶, Prudlo J^17,18, Jahn H^19,20, Boeckh-Behrens T²¹, Danek A¹, Klopstock T^7,9,22, Levin J^1,7. Collaborators (4) Abstract

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD.

KEYWORDS:

C9orf72; amyotrophic lateral sclerosis; atlas based volumetric MRI analysis; cerebellum; frontotemporal dementia; salience network; thalamus

PMID:

29599716

PMCID:

PMC5863593

DOI:

10.3389/fnagi.2018.00045

Free PMC Article

 

3) 

Transl Psychiatry. 2019 Jan 31;9(1):54. doi: 10.1038/s41398-019-0381-1.

FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations.

Diehl-Schmid J¹, Licata A², Goldhardt O², Förstl H², Yakushew I³, Otto M⁴, Anderl-Straub S⁴, Beer A⁴, Ludolph AC⁴, Landwehrmeyer GB⁴, Levin J^5,6, Danek A⁵, Fliessbach K^7,8, Spottke A^8,9, Fassbender K¹⁰, Lyros E¹⁰, Prudlo J¹¹, Krause BJ¹², Volk A¹³, Edbauer D^6,14, Schroeter ML^15,16, Drzezga A^17,18, Kornhuber J¹⁹, Lauer M²⁰; FTLDc Study Group, Grimmer T².Collaborators (15)

Abstract

C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, ¹⁸F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.

PMID:

30705258

PMCID:

PMC6355852

DOI:

10.1038/s41398-019-0381-1

[Indexed for MEDLINE]

Free PMC Article

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