Semantic Recollection in Parkinson’s Disease: Functional Reconfiguration and MAPT Variants

Abstract

Decline in semantic cognition in early stages of Parkinson’s disease (PD) is a leading risk factor for future dementia, yet the underlying neural mechanisms are not understood. The present study addressed this gap by investigating the functional connectivity of regions involved in semantic recollection. We further examined whether microtubule-associated protein tau (MAPT) risk variants, which may accelerate cognitive decline, altered the strength of regional functional connections. Cognitively normal PD and healthy elder controls underwent fMRI while performing a fame-discrimination task, which activates the semantic network. Analyses focused on disturbances in fame-modulated functional connectivity in PD for regions that govern semantic recollection and interrelated processes. Group differences were found in multiple connectivity features, which were reduced into principal components that reflected the strength of fame-modulated regional couplings with other brain areas. Despite the absence of group differences in semantic cognition, two aberrant connectivity patterns were uncovered in PD. One pattern was related to a loss in frontal, parietal, and temporal connection topologies that governed semantic recollection in older controls. Another pattern was characterized by functional reconfiguration, wherein frontal, parietal, temporal and caudate couplings were strengthened with areas that were not recruited by controls. Correlations between principal component scores and cognitive measures suggested that reconfigured frontal coupling topologies in PD supported compensatory routes for accessing semantic content, whereas reconfigured parietal, temporal, and caudate connection topologies were detrimental or unrelated to cognition. Increased tau transcription diminished recruitment of compensatory frontal topologies but amplified recruitment of parietal topologies that were unfavorable for cognition. Collectively, the findings provide a new understanding of early vulnerabilities in the functional architecture of regional connectivity during semantic recollection in cognitively normal PD. The findings also have implications for tracking cognitive progression and selecting patients who stand to benefit from therapeutic interventions.

Internetwork Connectivity Predicts Cognitive Decline in Parkinson’s and Is Altered by Genetic Variants

“…One speculation is that communications of the RFPN with attention and executive/semantic networks may be amplified in patients who have difficulty finding names due to failed automatic retrieval of semantic details, which could be a sign of impoverished representations of semantic content. This proposal is compatible with a task-activated fMRI study of semantic recollection ( Harrington et al, 2021 ). We found that stronger connectivity of a semantic hub and the caudate with regions comprising the dorsal attention, executive, and/or language systems correlated with poorer BNT performance in PDCN.…”

“…We found that stronger connectivity of a semantic hub and the caudate with regions comprising the dorsal attention, executive, and/or language systems correlated with poorer BNT performance in PDCN. These results suggested the possibility that patients with poorer naming may allocate more attention and executive resources to support covert verbal strategic searches needed to find names that cannot be retrieved automatically ( Harrington et al, 2021 ).…”

“…Knowledge about the pathophysiology behind cognitive changes in PD is largely based on people who already show mild cognitive impairment (MCI). Yet changes in the brain occur years before cognitive symptoms manifest ( Harrington et al, 2020 , 2021 ). As optimal treatments depend on early detection, markers of brain dysfunction that predate MCI and foreshadow the evolution of cognitive decline are sorely needed.…”

“…The present study investigated internetwork intrinsic functional connectivity in PDCN and healthy adults in core networks including the DMN, LFPN, RFPN, and SN. As the DMN is composed of subsystems that capture the heterogeneous nature of self-generated thoughts ( Andrews-Hanna et al, 2014b ), we studied the anterior DMN (aDMN), which supports self-generated executive, conceptual, and semantic processes relevant to PD ( Harrington et al, 2020 , 2021 ), and the posterior DMN (pDMN) which supports episodic and autobiographical memory, and associative or constructive processes. VN internetwork connectivity was studied as well since disturbances in visual cognition are a marker of future dementia ( Williams-Gray et al, 2013 ).…”

“…We predicted that SNCA expression would alter SN internetwork connectivity owing to accumulation of α-synuclein in the insula ( Christopher et al, 2014 ). Tau expression was expected to alter internetwork topologies comprised of frontal and posterior cortices (FPN, DMN, VN), which are modulated by MAPT variants ( Nombela et al, 2014 ; Harrington et al, 2021 ).…”