Identification of new biomarkers in ALS. Cognition in Motor Neuron Disease (DZNE ALS-FTD Initiative), extended data analysis

Key tasks within this intersite project are:
1.) To develop new clinical biomarkers in ALS (CSF, cerebral cortex, peripheral nerve, pain and dyspnoe management).To develop and review a German language neuropsychological test battery focussed on
2.) cognition and behaviour in ALS/ALS-FTD. This battery will have to detect cognitive changes independently form the motor disabilities.
3.) To define changes in cerebral fibre tracts, regional cortical atrophy and functional
connectivity in ALS with and without cognitive impairment, including ALS-FTD, relative to healthy sex and age matched controls using multimodal MR imaging (cross-sectional design).
4.) To define new biomarkers and brain network changes by structural or functional imaging as a predictor of mental and clinical changes in ALS patients (longitudinal design).
5.) To correlate structural or functional neuroimaging findings of specific network disruption and dysfunction with neuropsychological and autopsy data in order to characterize more precisely frontal and temporal lobe dysfunctions associated with ALS.

In Magdeburg, neuroimaging ALS projects comprise the application of high-resolution 3T to 7T-MRI and peripheral nervous system (PNS) ultrasound. Meso-scale layer- and column-specific imaging of the motor cortex applying MP2RAGE sequences and fMRI thereby aims to allow for a deeper understanding of the cortical representation of bulbar, fine and gross motor involvement as well as of differential neuromuscular patterns (e.g. "split hand”) in ALS. Fusion-imaging between PNS 7T-MR neurography and high-resolution ultrasound using new imaging markers such as e.g. fascicular T2-alterations, PNS DTI, microvascular blood flow and gray scale measures will further help to elucidate distinct stages of peripheral nerve degeneration and inflammation in ALS. Imaging findings together with further biomarkers, e.g. CSF NfL, will then be combined within higher order classification models to allow for the specific identification of certain ALS patients to stratify them according to their long-term functional status and prognosis.

From March 2011 to December 2020, the DZNE sites Magdeburg and Rostock were able to recruit over 200 ALS patients and 80 healthy controls. We have put into practice comprehensive clinical and neuropsychological test batteries that were associated with multimodal imaging findings at 3 and 7 Tesla. Our results demonstrated that memory functions in ALS can be deficient and seem to be linked to frontotemporal dysfunctions. We performed a DTI study in a neuropsychologically well characterized, large patient cohort. Our results indicate that frontotemporal white matter lesions correlate with cognitive impairments. ALS patients demonstrated cortical thinning not only in motor but also in extra-motor areas. Ultra-high-field magnetic resonance imaging investigations at 7 Tesla revealed different motor cortex involvement in a subpopulation of upper motor neuron (UMN) - dominant ALS and Primary Lateral Sclerosis (up to now 15 patients). The data set was analyzed and continuously published (see below). Furthermore, biomarker studies (CSF, ultrasound studies of peripheral nerves) were further extended and resulted in the below mentioned publications.