Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy

Abstract

Abnormalities of tau protein are central to the pathogenesis of progressive supranuclear palsy, whereas haplotype variation of the tau gene MAPT influences the risk of Parkinson disease and Parkinson's disease dementia. We assessed whether regional MAPT expression might be associated with selective vulnerability of global brain networks to neurodegenerative pathology. Using task-free functional magnetic resonance imaging in progressive supranuclear palsy, Parkinson disease, and healthy subjects (n = 128), we examined functional brain networks and measured the connection strength between 471 gray matter regions. We obtained MAPT and SNCA microarray expression data in healthy subjects from the Allen brain atlas. Regional connectivity varied according to the normal expression of MAPT. The regional expression of MAPT correlated with the proportionate loss of regional connectivity in Parkinson's disease. Executive cognition was impaired in proportion to the loss of hub connectivity. These effects were not seen with SNCA, suggesting that alpha-synuclein pathology is not mediated through global network properties. The results establish a link between regional MAPT expression and selective vulnerability of functional brain networks to neurodegeneration.

Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease

“…In agreement with our study, a previous analysis involving the ADNI cohort also found that baseline levels of CSF α -synuclein were not correlated to atrophy brain rates across the spectrum of normal aging, MCI, and AD (Mattsson et al., 2013). These findings, considered together with autopsy-confirmed reports of relatively preserved brain structure in Lewy body diseases (Nedelska et al., 2015), suggest that the effects of α -synuclein pathology may be mediated via cellular dysfunction and functional network disruption (Peraza et al., 2015, Rittman et al., 2016). These are important questions that will be further addressed by the future development of PET radioligands for α -synuclein (Eberling et al., 2013).…”

Radiological biomarkers for diagnosis in PSP: Where are we and where do we need to be?

“…MR modalities that demonstrate abnormalities in PSP‐RS include magnetic resonance spectroscopy and magnetization transfer imaging, although the ability of these modalities to differentiate PSP‐RS from other parkinsonian disorders is unclear . Resting‐state (task‐free) functional MRI has also been used to demonstrate abnormalities in functional connectivity in PSP‐RS across the network of PSP‐RS‐associated regions, but the loss of cortical connectivity is not specific to PSP‐RS versus PD . Longitudinal MR studies have shown increased rates of whole‐brain, cortical, and midbrain atrophy and SCP diffusivity in PSP‐RS compared with controls, with some evidence for greater rates than in PD, but similar rates of whole‐brain and midbrain atrophy as in MSA‐P .…”

“…181,184,185,205 Resting-state (task-free) functional MRI has also been used to demonstrate abnormalities in functional connectivity in PSP-RS across the network of PSP-RS-associated regions, 63,206,207 but the loss of cortical connectivity is not specific to PSP-RS versus PD. 208 Longitudinal MR studies have shown increased rates of whole-brain, cortical, and midbrain atrophy and SCP diffusivity in PSP-RS compared with controls, [209][210][211][212][213][214][215][216][217][218] with some evidence for greater rates than in PD, but similar rates of whole-brain and midbrain atrophy as in MSA-P. 212,215 However, cortical and whole-brain rates of atrophy are greater in CBS than in PSP-RS. 209,213 Cerebral blood flow single-photon emission computed tomography studies have demonstrated frontal [219][220][221][222][223][224][225] and, less commonly, thalamic 220 and striatal 222 hypoperfusion in PSP-RS.…”

The role of high‐field magnetic resonance imaging in parkinsonian disorders: Pushing the boundaries forward

“…Reduced functional activity was found in the contralateral caudate, primary motor and premotor cortex, and ipsilateral putamen in PSP when compared with PD . Highly connected cortical regions suffered a disproportionate loss of FC in PSP, which correlated with the regional expression of the gene MAPT . Specific changes in the connectivity of the dorsal midbrain and striatum also occurred in PSP, including corticostriatal connections that correlated with disease severity .…”

“…181 Highly connected cortical regions suffered a disproportionate loss of FC in PSP, which correlated with the regional expression of the gene MAPT. 182 Specific changes in the connectivity of the dorsal midbrain and striatum also occurred in PSP, including corticostriatal connections that correlated with disease severity. 181,183 These results suggest that the magnitude and topology of functional brain networks is changed by PD, PSP, and MSA.…”