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Background: Life expectancy is increasing, leading to a growing number of individuals affected by cognitive impairments. However, cognitive aging varies greatly: some individuals experience substantial decline, while others retain their cognitive abilities well into old age. Three early brain changes associated with cognitive decline are reduced dopamine function, cerebral small vessel disease (CSVD), and inflammation. Key knowledge gaps remain regarding how these processes are intertwined in healthy cognitive aging and whether some of these play a particularly important role in driving individualdifferences in cognition.

Aim: To examine the associations among dopamine decline, CSVD, and inflammation in healthy older adults, and the respective links between these processes and cognition. Sex differences are considered.

Methods: Data were drawn from two studies, referred to as COBRA and InflamAge. The COBRA study included data from 81 healthy adults (45% women) aged 64–68 years. Of these, 129 underwent a five-year follow-up. Dopamine D2-like receptors (DRD2) in the brain were measured using 11C-raclopride and positron emission tomography (PET). Peripheral inflammation was estimated via two DNA methylation-based inflammation scores. The InflamAge study has a cross-sectional design and included 55 older adults (60–79 years, 51% women). Dopamine transporter (DAT) availability was estimated with 18F-FE-PE2I/PET, and inflammation (specifically astrocyte reactivity) via 11C-L-deprenyl-D2/PET. The same cognitive test battery, magnetic resonance imaging (MRI) scanner, and protocols were used in the two studies. MRI was employed to evaluate markers of CSVD (lesions, lacunes, and perivascular space enlargement), brain volumes, and cerebral perfusion. Health-related factors (hypertension, BMI, and hyperlipidaemia) were also mapped.

Results: CSVD was a stable predictor of individual differences in dopaminergic integrity and emerged as a potential predictor of within-person dopamine decline rate over time. Cross-sectional analyses in both samples showed that higherwhite-matter lesion volumes were associated with reduced DRD2 and DAT availability. Longitudinal analyses in COBRA demonstrated that individuals with a higher burden of white matter lesions and lacunes showed the fastest DRD2 decline, while those spared of these manifestations were also spared of DRD2 decline. Hypertension was associated with lower DAT availability as well as faster DRD2 decline. Peripheral inflammation was also associated with individual differences in DRD2 availability, but only in men. As opposed to CSVD, peripheral inflammation did not predict the degree of prospective DRD2decline over 5 years. Astrocyte reactivity (generally considered a marker of neuroinflammation) was higher at older ages. Contrary to expectations, it was positively associated with DAT availability and negatively with CSVD. Regarding cognition, higher CSVD severity was associated with a trend for faster declining processing speed. When modelled together, DAT availability was the strongest and most significant predictor of general cognition. Sex differences were found for links between DRD2 and peripheral inflammation scores, but overall, findings were similar for men and women.

Conclusion: Dopaminergic integrity is key for several cognitive functions and is important to preserve in aging. Reduction of CSVD severity may serve as one viable intervention approach. The relationship between chronic inflammation and dopamine integrity remains inconclusive and should be further investigated in future work.

Several aging-related brain changes have been associated with unsuccessful cognitive aging, including dopamine decline, increased astrocyte reactivity, and cerebral small-vessel disease (SVD). We hypothesized that dopamine decline is exacerbated in older adults with higher measures of astrocyte reactivity and cerebral SVD, and that reduced dopamine integrity would be the strongest predictor of lower cognitive performance. Healthy adults (n = 55, ages: 60–79 years) underwent positron emission tomography with ligands 18F-FE-PE2I to estimate levels of dopamine transporters (DAT) and 11C-L-deprenyl-D2 to estimate levels of monoamine oxidase B (MAO-B)—a protein expressed to some degree by neurons but mainly by astrocytes. Cerebral SVD was assessed by white matter lesion volumes from magnetic resonance images. General cognition was evaluated via tests of episodic memory, working memory, and perceptual speed. Contrary to expectations, increased MAO-B levels (indicative of astrocyte reactivity) were associated with higher DAT availability (r = 0.53, p < 0.001) and reduced white matter lesion volumes (r = −0.33, p = 0.021). Reduced DAT availability was more strongly related to reduced MAO-B (r = 0.47, p < 0.001) than white matter lesion volumes (r = −0.22, p > 0.05), and only DAT was a significant predictor of cognition (r = 0.36, p = 0.032). These findings underscore the critical role of dopamine for cognition and indicate reduced glial function to underlie dopaminergic losses.

Background: Normal brain aging is associated with dopamine decline, which has been linked to age-related cognitive decline. Factors underlying individual differences in dopamine integrity at older ages remain, however, unclear. Here we aimed at investigating: (i) whether inflammation is associated with levels and 5-year changes of in vivo dopamine D2-receptor (DRD2) availability, (ii) if DRD2-inflammation associations differ between men and women, and (iii) whether inflammation and cerebral small-vessel disease (white-matter lesions) serve as two independent predictors of DRD2 availability.

Methods: Analyses were performed in a sample of healthy adults > 60 years assessed at two measurement occasions separated by 5 years. At both occasions, DRD2 availability was estimated by ¹¹C-raclopride PET, and white-matter lesions by MRI. Inflammation was assessed by two C-reactive protein-associated DNA methylation scores at study baseline.

Results: Individuals with higher DNA methylation scores at baseline showed reduced striatal DRD2 availability. An interaction was found between DNA methylation scores and sex in relation to striatal DRD2 availability, such that associations were found in men but not in women. DNA methylation scores at study entrance were not significantly associated with 5-year striatal DRD2 decline rates. No significant association was found between DNA methylation scores and white-matter lesions, but higher scores as well as higher lesion burden were independently associated with reduced striatal DRD2 availability in men.

Conclusions: These findings suggest negative associations between one proxy of inflammation and DRD2 availability in older adults, selectively for men who had higher DNA methylation scores. Future studies should investigate other inflammatory markers in relation to dopamine integrity.

Normal aging is associated with decline in dopamine function. Factors associated with individual differences in dopamine decline rates remain unclear but are important to map to spare dopamine-related functions, such as cognition. Here we focused on manifestations of cerebral small-vessel disease from magnetic resonance imaging (white-matter lesions, lacunes, and perivascular space dilation) and vascular risk factors (e.g., hypertension, body mass index (BMI), and hyperlipidemia). We assessed striatal dopamine D2-like receptor (DRD2) reductions across five years in healthy, older adults (n = 129, ages: 64–68 years at baseline) using 11C-raclopride/positron emission tomography. Manifestations of confluent lesions and lacunes at baseline had additive effects on DRD2 decline. Individuals with both manifestations showed fastest DRD2 decline rates (∼ −4 %), followed by those with one manifestation (∼ −2 %), whereas individuals spared of confluent lesions and lacunes showed stable DRD2 levels over time (∼ 0 % change). Furthermore, individuals with confluent lesions or lacunes showed more marked decline in perceptual speed performance, as compared to individuals spared of these manifestations (p < 0.05). Higher systolic blood pressure and lower BMI at baseline were associated with faster 5-year DRD2 decline in the putamen (r = -0.17, p < 0.05) and caudate (r = 0.23, p < 0.05), respectively. Together, confluent lesions and lacunes explained up to 8 % of striatal DRD2 change, and up to 10 % when adding hypertension and BMI to the model. These findings suggest that hallmarks of SVD and certain vascular risk factors predispose faster DRD2 decline in aging and may thus serve as factors to consider in future interventions.

OBJECTIVES: To provide an overview of patient and public involvement (PPI) in the mesolevel and macrolevel of healthcare (different from PPI in research) and identify directions for future research by mapping contexts, terminology, conceptual frameworks, measured outcomes and research gaps.

DESIGN: Mapping review of systematic reviews. A patient coresearcher (JB) was involved in all stages. A broad search strategy was applied to capture the variation in terminology.

DATA SOURCES: MEDLINE, CINAHL and PsycINFO were searched from 1 January 2001 to 5 December 2022.

ELIGIBILITY CRITERIA: We included systematic reviews of empirical studies focusing on PPI in the mesolevel and macrolevel of healthcare.

DATA EXTRACTION AND SYNTHESIS: Three independent reviewers used standardised methods to screen studies and extract data. Thematic categories were created inductively through iteration. The results were organised in narrative, visual or tabular formats.

RESULTS: 4419 identified records were screened. 37 systematic reviews were eligible for inclusion. Most studies were narrative syntheses (N=26). Identified context categories were PPI for healthcare quality improvement (22%), patient safety (8%), community-based initiatives (27%), peer support (16 %) and education of healthcare professionals (27%). A wide range of terms was used to discuss PPI, with community participation being the most common. 28 reviews reported on frameworks, conceptual guidance and/or policy documents. Nine different types of outcomes were identified. The research gap pointed out most frequently is the lack of studies of robust designs that allow for replication and long-term follow-up, followed by studies on cost-effectiveness and resources needed. There is a need for consensus on the use of terminology.

CONCLUSIONS: This mapping review sheds light on the evolving landscape of PPI in healthcare. To advance the field, future research should prioritise rigorous study designs, cost-effectiveness assessments and consensus-building efforts to create a more unified and impactful approach for PPI in healthcare.