Network spread determines severity of degeneration and disconnection in Huntington's disease

Poudel, Govinda; Harding, Ian H.; Egan, Gary F.; Georgiou‐Karistianis, Nellie

doi:10.1002/hbm.24695

Cited by 50 publications

(53 citation statements)

References 46 publications

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“…Using longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, Torok and colleagues (2018) showed that NDM and an inference optimization algorithm can successfully infer the regions of disease initiation (referred as seed regions) from which Alzheimer’s disease or Mild Cognitive Impairment tau pathology most likely originated. Our recent study demonstrated that the spread of mutant huntingtin protein, via the human brain connectome, accurately predicted the cortico‐striatal spatial pattern of degeneration in patients with Huntington’s disease. The NDM framework was also recently used for capturing the spatiotemporal progression of Parkinson’s disease .…”

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

“…The present study employed a model of spread of pathology via brain networks based on the network diffusion model (NDM) . A growing number of studies have utilized NDM as a means to model the progression of neurodegenerative pathology on brain networks . Using longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, Torok and colleagues (2018) showed that NDM and an inference optimization algorithm can successfully infer the regions of disease initiation (referred as seed regions) from which Alzheimer’s disease or Mild Cognitive Impairment tau pathology most likely originated.…”

Section: Introductionmentioning

confidence: 99%

“…8,12 A growing number of studies have utilized NDM as a means to model the progression of neurodegenerative pathology on brain networks. [9][10][11][12][13][14][15] Using longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, Torok and colleagues (2018) 15 showed that NDM and an inference optimization algorithm can successfully infer the regions of disease initiation (referred as seed regions) from which Alzheimer's disease or Mild Cognitive Impairment tau pathology most likely originated. Our recent study 12 demonstrated that the spread of mutant huntingtin protein, via the human brain connectome, accurately predicted the cortico-striatal spatial pattern of degeneration in patients with Huntington's disease.…”

Section: Introductionmentioning

confidence: 99%

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Network diffusion modeling predicts neurodegeneration in traumatic brain injury

Poudel

Verhelst

et al. 2020

Ann Clin Transl Neurol

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Objective Traumatic brain injury (TBI) is a heterogeneous disease with multiple neurological deficits that evolve over time. It is also associated with an increased incidence of neurodegenerative diseases. Accordingly, clinicians need better tools to predict a patient’s long‐term prognosis. Methods Diffusion‐weighted and anatomical MRI data were collected from 17 adolescents (mean age = 15y8mo) with moderate‐to‐severe TBI and 19 healthy controls. Using a network diffusion model (NDM), we examined the effect of progressive deafferentation and gray matter thinning in young TBI patients. Moreover, using a novel automated inference method, we identified several injury epicenters in order to determine the neural degenerative patterns in each TBI patient. Results We were able to identify the subject‐specific patterns of degeneration in each patient. In particular, the hippocampus, temporal cortices, and striatum were frequently found to be the epicenters of degeneration across the TBI patients. Orthogonal transformation of the predicted degeneration, using principal component analysis, identified distinct spatial components in the temporal–hippocampal network and the cortico‐striatal network, confirming the vulnerability of these networks to injury. The NDM model, best predictive of the degeneration, was significantly correlated with time since injury, indicating that NDM can potentially capture the pathological progression in the chronic phase of TBI. Interpretation These findings suggest that network spread may help explain patterns of distant gray matter thinning, which would be consistent with Wallerian degeneration of the white matter connections (i.e., “diaschisis”) from diffuse axonal injuries and multifocal contusive injuries, and the neurodegenerative patterns of abnormal protein aggregation and transmission, which are hallmarks of brain changes in TBI. NDM approaches could provide highly subject‐specific biomarkers relevant for disease monitoring and personalized therapies in TBI.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Network diffusion modeling predicts neurodegeneration in traumatic brain injury

Poudel

Verhelst

et al. 2020

Ann Clin Transl Neurol

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“…Post-mortem histopathological analyses (Braak and Braak, 1991; Braak et al, 2003; Brettschneider et al, 2013) and in vivo imaging studies (Deng et al, 2004; Poudel et al, 2019) indicate that proteopathic lesions associated with neurodegeneration appear in highly-reproducible and disease-specific spatiotemporal patterns through the brain. Interestingly, these patterns largely follow neuroanatomical tracts (Ahmed et al, 2014; Mezias et al, 2017), suggesting a central role for synaptic connectivity in pathological aggregate spreading.…”

Section: Introductionmentioning

confidence: 99%

Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

Donnelly

DeLorenzo

Zaya

et al. 2019

Preprint

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14Emerging evidence supports the hypothesis that pathogenic protein aggregates associated with 15 many neurodegenerative diseases spread from cell to cell through the brain in a manner akin to 16 infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington 17 disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila 18 olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal 19 activity and blocked by caspase inhibition in presynaptic neurons, implicating synaptic dysfunction and 20 cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires 21 the scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that 22 phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected 23 neurons. These findings expand our understanding of phagocytic glia as double-edged players in 24 neurodegeneration-they clear neurotoxic protein aggregates, but also provide opportunities for prion-25 like seeds to evade phagolysosomal degradation and propagate further in the brain. 26 93 5 RESULTS 94Anterograde transfer of prion-like mHtt aggregates across synapses in the adult fly olfactory system 95 Aggregates formed by N-terminal fragments of mHtt generated by aberrant splicing (e.g., exon 96 1; Httex1) (Sathasivam et al., 2013) or caspase cleavage (e.g., exon 1-12; Httex1-12) (Graham et al., 2006) 97 (Fig. 1A) accumulate in HD patient brains, are highly cytotoxic, and spread between cells in culture and 98 in vivo (Babcock and Ganetzky, 2015; Costanzo et al., 2013; Pearce et al., 2015; Pecho-Vrieseling et 99 al., 2014; Ren et al., 2009). We have previously established transgenic Drosophila that employ binary 100 expression systems [e.g., Gal4-UAS, QF-QUAS, or LexA-LexAop (Riabinina and Potter, 2016)] to 101 express fluorescent protein (FP) fusions of Httex1 in non-overlapping cell populations in order to monitor 102 cell-to-cell transfer of mHttex1 aggregates in intact brains (Donnelly and Pearce, 2018; Pearce et al., 103 2015). Our experimental approach (Fig. 1B) exploits the fact that wtHttex1 proteins only aggregate upon 104 encountering mHttex1 aggregate seeds (Chen et al., 2001; Preisinger et al., 1999), such that transfer of 105 mHttex1 aggregates from "donor" cells is reported by conversion of cytoplasmic wtHttex1 from its normally 106 soluble, diffuse state to a punctate, aggregated state in "acceptor" cells. To confirm that mHttex1 107 nucleates the aggregation of wtHttex1 in fly neurons, we co-expressed FP-fusions of these two proteins 108 using pan-neuronal elav[C155]-Gal4. In flies expressing only mCherry-tagged mHttex1 (Httex1Q91-109 mCherry) pan-neuronally, aggregates were visible as discrete mCherry+ puncta throughout neuronal 110 cell bodies and neuropil regions of adult fly brains ( Fig. 1-figure supplement 1A). By contrast, GFP-111 tagged wtHttex1 (Httex1Q25-GFP) was expressed di...

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Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Reyes

Pulverenti

et al. 2020

Ann Clin Transl Neurol

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Background Recent findings suggest that individuals with Huntington’s disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear. Objectives To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments. Methods Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment. Results Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test–retest reliability [ICC: 0.61‐0.99] for individuals with presymptomatic and prodromal HD and healthy controls. Conclusions Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls.

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Network spread determines severity of degeneration and disconnection in Huntington's disease

Cited by 50 publications

References 46 publications

Network diffusion modeling predicts neurodegeneration in traumatic brain injury

Network diffusion modeling predicts neurodegeneration in traumatic brain injury

Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

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