Network connectivity determines cortical thinning in early Parkinson’s disease progression

Abstract

Here we test the hypothesis that the neurodegenerative process in Parkinson’s disease (PD) moves stereotypically along neural networks, possibly reflecting the spread of toxic alpha-synuclein molecules. PD patients (n = 105) and matched controls (n = 57) underwent T1-MRI at entry and 1 year later as part of the Parkinson’s Progression Markers Initiative. Over this period, PD patients demonstrate significantly greater cortical thinning than controls in parts of the left occipital and bilateral frontal lobes and right somatomotor-sensory cortex. Cortical thinning is correlated to connectivity (measured functionally or structurally) to a “disease reservoir” evaluated by MRI at baseline. The atrophy pattern in the ventral frontal lobes resembles one described in certain cases of Alzheimer’s disease. Our findings suggest that disease propagation to the cortex in PD follows neuronal connectivity and that disease spread to the cortex may herald the onset of cognitive impairment.

Longitudinal brain atrophy distribution in advanced Parkinson's disease: What makes the difference in “cognitive status” converters?

“…We demonstrated almost the same atrophy progression rate in our PD cohort regardless of the cognitive status which is apparently at odds with previous longitudinal studies in PD that reported accelerated atrophy progression in PD (Mak et al, 2015;Yau et al, 2018)the main difference is, however, that these studies enrolled newly diagnosed PD or de-novo PD patients. Our data were generated within the LANDSCAPE study aiming at identifying factors which contribute to both the evolution and progression of cognitive impairment in PD (Balzer-Geldsetzer et al, 2011) so that patients with and without dementia were eligible for enrolment which resulted in a cohort of advanced patients.…”

“…By definition, longitudinal studies from postmortem material are not possible, hence, tracing the temporal dynamics of pathology patterns in vivo together with clinical features becomes increasingly important (Fereshtehnejad, Zeighami, Dagher, & Postuma, 2017). The regional pattern of cortical brain atrophy in PD remarkably resembles the spatial distribution of cognition-related "resting-state" fMRI networks (Zeighami et al, 2015), and the atrophy distribution appears to be predicted by hyperconnective pathways (Yau et al, 2018). Following longitudinal studies in PD patients that demonstrated a regionspecific accelerated cortical thinning (Mak et al, 2015), we were encouraged to test the hypothesis whether the rate of volumetric changes and cortical thinning over time allows for the definition of a cognitive status-dependent pattern in advanced PD.…”

“…The LOWESS plot indicated (a) a steady atrophy progression of approximately 5cm 3 per year (~0.5% per year) for the overall brain volume in healthy elderly over about 60 years (*) and for patients independent of age. (b) The rate of cortical thinning for mean cortical thickness in healthy elderly controls (approximately 7.3 μm per year over about 60 years of age *) and PD patients without (PD-N) and with cognitive deficits (PD-CI)In the interest of comparability with previous studies(Mak et al, 2015;Yau et al, 2018), longitudinal thickness analysis at 1-year follow-up was performed and indicated an almost similar rate of mean cortical thinning by about −30 μm per year across groups, that is, PD-N (n = 68) and PD-CI patients (n = 61) compared to healthy controls (n = 66), as indicated by Kruskal-Wallis analysis on ranks (χ 2 = 0.68, p = .711). The use of a general linear model (GLM) according to Freesurfer's longitudinal processing pipeline(Reuter, Schmansky, Rosas, & Fischl, 2012) resulted in no significant differences in regionspecific rate of cortical thickness changes at 1-year follow-up between PD-patients (n = 127) and controls (n = 66).Overall, the longitudinal analyses of volumetric and cortical thickness measures indicated an almost identical atrophy progression in advanced PD patients relative to "normal" aging regardless of whether patients were neuropsychologically classified as cognitively unimpaired or impaired.…”

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

“…In many respects, the reduced complexity of the models offers a unique opportunity for experimental control. However, the absence of neuronal and cellular networks, synaptic communication, are also relevant limitations of in vitro studies (Yau et al 2018).…”

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

“…For example, trans-synaptic transfer of mHTT, involving synaptic vesicle exocytosis (Pecho-Vrieseling et al, 2014), have been demonstrated in a mouse model of mHTT. Previous studies have mapped the brain connectome using diffusion weighted imaging (DWI) based tractography and used it to predict network vulnerability in Alzheimer's and Parkinson's diseases (Raj et al, 2015;Raj, Kuceyeski, & Weiner, 2012;Yau et al, 2018). These studies clearly highlight the role of axonal connections in mHTT spread, motivating the hypothesis that the canonical organisation of the axonal connections (human brain connectome) may determine the pattern of neuropathological changes in the HD brain.…”