Challenging the Functional Connectivity Disruption in Neurodegenerative Diseases: New Therapeutic Perspectives through Non-Invasive Neuromodulation and Cutting-Edge Technologies

Recent research has demonstrated the importance of global changes to the functional organization of brain network following stroke. Resting functional magnetic resonance imaging (R-fMRI) is a non-invasive tool that enables the measurement of functional connectivity (FC) across the entire brain while placing minimal demands on the subject. For these reasons, it is a uniquely appealing tool for studying the distant effects of stroke. However, R-fMRI studies rely on a number of premises that cannot be assumed without careful validation in the context of stroke. Here, we describe strategies to identify and mitigate confounds specific to R-fMRI research in cerebrovascular disease. Five main topics are discussed: (a) achieving adequate co-registration of lesioned brains, (b) identifying and removing hemodynamic lags in resting BOLD, (c) identifying other vascular disruptions that affect the resting BOLD signal, (d) selecting an appropriate control cohort, and (e) acquiring sufficient fMRI data to reliably identify FC changes. For each topic, we provide guidelines for steps to improve the interpretability and reproducibility of FC-stroke research. We include a table of confounds and approaches to identify and mitigate each. Our recommendations extend to any research using R-fMRI to study diseases that might alter cerebrovascular flow and dynamics or brain anatomy.

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Linking Enzyme Upregulation to Autophagic Failure: A Potential Biomarker for GM1 Gangliosidosis

10.1101/2020.10.28.359083 ◽

2020 ◽

Author(s):

Sarah Smith ◽

Jessica Larsen

Keyword(s):

Enzyme Activity ◽

Neurodegenerative Diseases ◽

Lysosomal Storage ◽

Gm1 Gangliosidosis ◽

Non Invasive ◽

Potential Biomarker ◽

Significant Difference ◽

Hexosaminidase A ◽

Normal Enzyme ◽

Normal Enzyme Activity

AbstractWith an increasing aging population, neurodegenerative diseases are having an increased impact on society. Typically, these diseases are diagnosed significantly past symptom onset, decreasing the possibility of effective treatment. A non-invasive biomarker and specific target are needed to diagnose and treat the disease before late-stage symptoms. GM1 Gangliosidosis is a lysosomal storage disease where lysosomal enzyme β-galactosidase is missing. As a result, GM1 ganglioside is not broken down and accumulates in the cell, ultimately leading to cell death. One of the main aspects of GM1 Gangliosidosis, and other neurodegenerative diseases, is impaired autophagy: reduced fusion of autophagosomes and lysosomes to degrade cellular waste.In this paper, we show that healthy cells (NSV3) have approximately 13 times more co-localization of lysosomes and autophagosomes than GM1 Gangliosidosis-diseased cells (GM1SV3), as demonstrated via immunofluorescence. GM1SV3 fold normal enzyme activity of β-galactosidase was downregulated while mannosidase, and hexosaminidase A were both upregulated. When inducing impaired autophagy in NSV3 via starvation, co-localization gradually decreases with increased starvation time. Most notably, after 48-hour starvation, healthy cells (NSV3) showed no significant difference in co-localization compared to GM1SV3. NSV3 under starvation conditions showed a significant increase between time starved and fold normal enzyme activity, with a positive correlation being observed. Activities of mannosidase, and hexosaminidase A of starved NSV3 closely resemble, and surpass, GM1SV3 after 12-hour starvation.These observations have the potential to expand the conversation regarding impaired autophagy as a potential biomarker for disease progression and diagnostics and as a treatment target.

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