Abstract
Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients’ cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease in the population aged over 65 years
In sporadic PD, cognitive impairment has been shown to occur since early clinical stages, probably following a long non-symptomatic period of brain compensation
As previously suggested, Montreal Cognitive Assessment battery (MoCA) is highly sensitive in detecting cognitive deficits in PD [33], and this might account for inconsistences across studies
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease in the population aged over 65 years. Researchers have put increasing efforts to clarify the pathophysiology of cognitive impairment in PD and, to this aim, the availability of a condition mimicking preclinical stages in humans is of great interest Relevant progress in this field has come from studies of mendelian forms of parkinsonism, in particular those recessively inherited. Single heterozygous mutations in Park and PINK1 genes can be identified in patients with features indistinguishable from sporadic, late-onset PD, as well as in non-symptomatic individuals [4]. There is growing evidence indicating that even non-symptomatic heterozygous carriers (i.e., relatives of patients with biallelic mutations) often present with subtle signs of dopaminergic dysfunction, as demonstrated by Photon Emission Tomography and functional MR imaging (fMRI) [5,6] These individuals provide a unique model for in vivo research into the pre-clinical stages of PD. In a genetic variant of frontotemporal dementia, FC was shown to play in distinct networks either a pathogenetic or a compensatory role when assessed at preclinical or clinical stages of disease [19]
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