Dopamine D1-Receptor Organization Contributes to Functional Brain Architecture.

Recent work has recognized a gradient-like organization in cortical function, spanning from primary sensory to transmodal cortices. It has been suggested that this axis is aligned with regional differences in neurotransmitter expression. Given the abundance of dopamine D1-receptors (D1DR), and its importance for modulation and neural gain, we tested the hypothesis that D1DR organization is aligned with functional architecture, and that inter-regional relationships in D1DR co-expression modulate functional cross talk. Using the world's largest dopamine D1DR-PET and MRI database (N = 180%, 50% female), we demonstrate that D1DR organization follows a unimodal-transmodal hierarchy, expressing a high spatial correspondence to the principal gradient of functional connectivity. We also demonstrate that individual differences in D1DR density between unimodal and transmodal regions are associated with functional differentiation of the apices in the cortical hierarchy. Finally, we show that spatial co-expression of D1DR primarily modulates 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.

Change in cardiovascular health and rate of cognitive decline in older adults: a 15-year population-based study.

BACKGROUND: Previous research on associations between cardiovascular health, measured at a single timepoint, and rate of age-related cognitive decline shows divergent findings dependent on the participants' age and the health metric studied. The aim of this study was to add to the knowledge in this field by investigating whether change in cardiovascular health, assessed with Life's Simple 7 (LS7) score, is associated with rate of cognitive change in young-old and old-old adults. METHODS: The study included 1022 participants aged ≥ 60 years from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic memory, semantic memory, verbal fluency, and perceptual speed) across up to 15 years. LS7, composed of seven cardiovascular health metrics (smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure), was assessed at baseline and at the 6-year follow-up. Change in LS7 was calculated as the difference between baseline and 6 years (range - 5 to 8 points) and categorised into worse (-5 to -2 points), stable (-1 to 1 points), and improved (2 to 8 points). Change in cognitive performance as a function of LS7 change categories was estimated using linear mixed-effects models. RESULTS: Participants were classified as stable (67.1%), improved (21.0%), or worse (11.8%) according to changes in LS7 score. Both the worse and improved categories were associated with faster cognitive decline. Age-stratified analyses revealed that worsening of LS7 was clearly associated with faster cognitive decline in the old-old (≥ 78 years), whereas improvement tended be associated with faster cognitive decline in the young-old (< 78 years) group. CONCLUSIONS: Change in cardiovascular health in old age may lead to accelerated cognitive decline, particularly in late senescence. These results suggest that it is important to monitor and maintain cardiovascular health status in very old adults.

Predictors of cognitive aging profiles over 15 years: A longitudinal population-based study.

The present study aimed to characterize profiles of cognitive aging and how these can be predicted from interindividual differences in demographic, lifestyle, health, and genetic factors. The participants were 1,966 older adults (mean baseline age = 71.6 years; 62.9% female), free from dementia at baseline and with at least two cognitive assessments over the 15-year follow-up, from the population-based Swedish National Study on Aging and Care in Kungsholmen. The cognitive assessment comprised tests of semantic and episodic memory, letter and category fluency, perceptual speed, and executive function. First, we estimated the level and change within each of the cognitive domains with linear mixed effect models, based on which we grouped our sample into participants with "maintained high cognition," "moderate cognitive decline," or "accelerated cognitive decline." Second, we analyzed determinants of group membership within each cognitive domain with multinomial logistic regression. Third, group memberships within each cognitive domain were used to derive general cognitive aging profiles with latent class analysis. Fourth, the determinants of these profile memberships were analyzed with multinomial logistic regression. Follow-up analyses targeted profiles and predictors specifically related to the rate of cognitive change. We identified three latent profiles of overall cognitive performance during the follow-up period with 31.6% of the sample having maintained high cognition, 50.6% having moderate cognitive decline, and 17.8% having accelerated cognitive decline. In multiadjusted analyses, maintained high cognition was predicted by female sex, higher education, and faster walking speed. Smoking, loneliness, and being an ε4 carrier were associated with a lower likelihood of maintained high cognition. Higher age, diagnosis of diabetes, depression, and carrying the apolipoprotein E ε4 allele increased the likelihood of accelerated cognitive decline. Factors at baseline that could significantly predict profile membership within the specific cognitive domains included age, sex, years of education, walking speed, diabetes, and the ε4 allele. Of note, these factors differed across cognitive domains. In sum, we identified demographic, lifestyle, health, and genetic factors of interindividual differences in domain-specific and general cognitive aging profiles, some of which are modifiable. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The influence of hippocampal dopamine D2 receptor losses on episodic-memory decline across 5 years is moderated by BDNF and KIBRA polymorphisms.

Losses in dopamine (DA) functioning may contribute to aging-related decline in cognition. Hippocampal DA is necessary for successful episodic memory formation. Previously, we reported that higher DA D2 receptor (D2DR) availability in hippocampus is beneficial for episodic memory only in older carriers of more advantageous genotypes of well-established plasticity-related genetic variations, the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. Extending our observations to the longitudinal level, the current data show that individuals with one or no beneficial BDNF and KIBRA genotype (n = 80) decline more in episodic memory across five years, without any contribution of losses in hippocampal D2DR availability to memory decline. Although carriers of two beneficial genotypes (n = 39) did not decline overall in episodic memory, losses of hippocampal D2DR availability were predictive of episodic-memory decline among these individuals. Our findings have implications for interventions targeting DA modulation to enhance episodic memory in aging, which may not benefit all older individuals.

Cardiovascular health and rate of cognitive decline in preclinical dementia: A 12-year population-based study.

OBJECTIVE: We investigated whether vascular risk factors (VRFs), assessed with Life's Simple 7 (LS7), are associated with the rate of cognitive decline in the years preceding a dementia diagnosis. METHOD: This study included 1,449 stroke-free participants aged ≥60 years from the Swedish National Study on Aging and Care in Kungsholmen, who underwent repeated neuropsychological testing (episodic memory, semantic memory, verbal fluency, perceptual speed) across 12 years. The LS7 score, assessed at baseline, included smoking, diet, physical activity, body mass index, plasma glucose, total cholesterol, and blood pressure. Preclinical dementia was defined as being dementia-free at baseline and diagnosed with dementia during follow-up. Level and change in cognitive performance as a function of LS7 category (poor vs. intermediate to optimal) and future dementia status were estimated using linear mixed-effect models. RESULTS: Participants who later developed dementia had, on average, a poorer LS7 score compared to those who remained dementia-free. For individuals aged 60-72 years, poor diet was associated with accelerated decline in perceptual speed (ß = -0.05, 95% CI [-0.08, -0.02]), and a poor glucose score was associated with faster rates of verbal fluency (ß = -0.019, 95% CI [-0.09, -0.01]) and global cognitive (ß = -0.028, 95% CI [-0.06, 0.00]) decline in the preclinical dementia group. CONCLUSIONS: VRFs exacerbate rate of cognitive decline in the years preceding a dementia diagnosis. This effect was most pronounced in young-old age and primarily driven by diet and glucose. The effect of VRFs may be especially detrimental for cognitive decline trajectories of individuals with impending dementia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Longitudinal support for the correlative triad among aging, dopamine D2-like receptor loss, and memory decline.

Dopamine decline is suggested to underlie aging-related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5-year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64-68 years; 5-year follow-up: n = 129) who underwent positron emission tomography with 11C-raclopride to assess dopamine D2-like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A data-driven approach (k-means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age-sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide-ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5-year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging.