No abstract

Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging.Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5-year longitudinal study spanning the adult human lifespan. DyNAMiC examines age-related changes in the brain's structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age-sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20-80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [ 11 C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [ 11 C]raclopride PET measuring D2DR. Age-related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u-shaped association between D1DR and resting-state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age-related cognitive decline.

The dopamine (DA) system, particularly D1-like DA receptors (D1DR), declines across the adult life. The functional consequences of reduced D1DR has been hypothesized to vary across life periods, but the precise timing of these periods is unknown. To examine distinct phases in age-related D1DR reductions, we studied 180 healthy adults (90 females, 20-80 years), who underwent D1DR PET assessment using [11C]SCH23390. A bi-phasic pattern of age-related D1DR differences was revealed, with an inflection point at approximately 40 years of age. Notably, D1DR levels before and after the inflection showed opposing relations to neurocognitive functions, in concordance with distinct consequences of D1DR differences during development and in old age. Furthermore, D1DR reductions in later life were linked to age-related cerebrovascular consequences. These results support a distinction between D1DR reductions in early adulthood from those later in life, and suggest less dramatic and more malleable DA losses in aging than previously suggested.

Decades of research on functional brain mapping have highlighted the importance of understanding the functional organization of the cerebral cortex. Recent studies have revealed a gradient of functional organization spanning from primary sensory to transmodal cortices. This gradient-like axis of connectivity has been hypothesized to be aligned with regional differences in the density of neuromodulatory receptors. Recent work in non-human primates supports this notion, revealing a gradient of dopamine D1-like receptor (D1DR) density along the cortical hierarchy. Given the importance of dopaminergic modulation for synaptic activity and neural gain, we tested whether D1DR shares the same organizational principles as brain function in humans, and whether inter-regional relationships in D1 expression modulate functional crosstalk. Using the world's largest combined dopamine D1DR-PET and MRI database, we provided empirical support for the first time in humans that the landscape of D1DR availability follows a unimodal-transmodal cortical hierarchy, with greater D1DR expression in associative cortical regions. We found an organization of inter- regional D1DR co-expression spanning unimodal to transmodal brain regions, expressing a high spatial correspondence to the principal macroscale gradient of functional connectivity. Critically, individual differences in D1DR density between unimodal and transmodal regions was associated with greater functional differentiation of the apices of the cortical hierarchy. Finally, inter-regional D1DR co-expression was found to modulate couplings within, but not between, functional networks. Together, our results show that D1DR co-expression provides a biomolecular layer to the functional organization of the brain.

The hippocampus is a complex structure critically involved in numerous behavior-regulating systems. A multidimensional account of the hippocampus functional integration with neocortex, however, remains to be established and evaluated in terms of functional specialization and cognitive decline in aging. Here, we identify two long-axis modes of cortical functional connectivity (FC) during rest: a principal gradient of gradual anterior-posterior variation reflecting a task-positive/task-negative cortical motif, and a second-order gradient, representing unimodal-transmodal macroscale cortical organization. The second-order gradient predicted episodic memory and reflected underlying distribution of postsynaptic dopamine D1 receptors, suggesting shared principles of functional and neuromolecular organization. Older age was associated with less distinct transitions in FC along gradients, and a youth-like gradient profile, i.e. maintained distinctiveness, was linked to superior memory, highlighting age-related gradient dedifferentiation as a potential marker of cognitive decline. Our results support the notion that hippocampal function stands to inform general principles of brain organization, and emphasize a critical role of a second-order long-axis connectivity mode in mnemonic function across the lifespan.