| 1. |
- Ekmark-Lewén, Sara, et al.
(författare)
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Reduction of brain stem pathology and transient amelioration of early cognitive symptoms in transgenic mice treated with a monoclonal antibody against α-synuclein oligomers/protofibrils
- 2023
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Ingår i: AGING BRAIN. - : Elsevier. - 2589-9589. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy against alpha-synuclein (alpha-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related alpha-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic alpha-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] alpha-syn transgenic mice. Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated alpha-syn (pS129 alpha-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target alpha-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other alpha-synucleinopathies.
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| 2. |
- Johansson, Jarkko, et al.
(författare)
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Cerebrovascular integrity affects gradients of aging-related dopamine D1 differences in the striatum
- 2023
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Ingår i: Aging Brain. - 2589-9589. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Extant research suggest aging-related losses of different dopaminergic markers, including presynaptic dopamine transporters as well as post-synaptic DA receptors. Given the central role of DA in neurocognitive functions, maintenance of a healthy DA system may be a key to mitigate age-related cognitive decline. Mechanisms behind DA losses in aging are however largely uncharted. Past research documented an association between dopaminergic integrity and cerebrovascular health (via white matter lesion volumes). However, it remains unclear whether proximity to lesions affected the spatial patterns of age-related D1DR differences within the striatum, and whether such differences are related to mnemonic function. Here, a large cohort of middle-aged to older healthy participants (age = 40–80 years, n = 119, 50 % women) was assessed for D1-receptor (D1DR) availability with positron emission tomography using [11C]SCH23390, and for white matter lesions using FLAIR-MRI. We found evidence for variations in degree of age-related differences along the ventro-dorsal axis, with more pronounced differences in the dorsal caudate. Further analyses revealed an association between distance to lesions and extent of D1DR losses in the caudate. Furthermore, D1DR differences in dorsal caudate (proximal to lesions) was more strongly associated with memory performance. In conclusion, the present findings suggest that maintenance of cerebrovascular health may be a key factor in promoting successful dopaminergic and memory aging.
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| 3. |
- Johansson, Jarkko, et al.
(författare)
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Model of brain maintenance reveals specific change-change association between medial-temporal lobe integrity and episodic memory
- 2022
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Brain maintenance has been identified as a major determinant of successful memory aging. However, the extent to which brain maintenance in support of successful memory aging is specific to memory-related brain regions or forms part of a brain-wide phenomenon is unresolved. Here, we used longitudinal brain-wide gray matter MRI volumes in 262 healthy participants aged 55 to 80 years at baseline to investigate separable dimensions of brain atrophy, and explored the links of these dimensions to different dimensions of cognitive change. We statistically adjusted for common causes of change in both brain and cognition to reveal a potentially unique signature of brain maintenance related to successful memory aging. Critically, medial temporal lobe (MTL)/hippocampal change and episodic memory change were characterized by unique, residual variance beyond general factors of change in brain and cognition, and a reliable association between these two residualized variables was established (r = 0.36, p < 0.01). The present study is the first to provide solid evidence for a specific association between changes in (MTL)/hippocampus and episodic memory in normal human aging. We conclude that hippocampus-specific brain maintenance relates to the specific preservation of episodic memory in old age, in line with the notion that brain maintenance operates at both general and domain-specific levels.
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| 4. |
- Luigi, Lorenzini, et al.
(författare)
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Gray matter network properties show distinct associations with CSF p-tau 181 levels and amyloid status in individuals without dementia.
- 2022
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Ingår i: Aging brain. - : Elsevier BV. - 2589-9589. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Gray matter networks are altered with amyloid accumulation in the earliest stage of AD, and are associated with decline throughout the AD spectrum. It remains unclear to what extent gray matter network abnormalities are associated with hyperphosphorylated-tau (p-tau). We studied the relationship of cerebrospinal fluid (CSF) p-tau181 with gray matter networks in non-demented participants from the European Prevention of Alzheimer's Dementia (EPAD) cohort, and studied dependencies on amyloid and cognitive status. Gray matter networks were extracted from baseline structural 3D T1w MRI. P-tau181 and abeta were measured with the Roche cobas Elecsys System. We studied the associations of CSF biomarkers levels with several network's graph properties. We further studied whether the relationships of p-tau 181 and network measures were dependent on amyloid status and cognitive stage (CDR). We repeated these analyses for network properties at a regional level, where we averaged local network values across cubes within each of 116 areas as defined by the automated anatomical labeling (AAL) atlas. Amyloid positivity was associated with higher network size and betweenness centrality, and lower gamma, clustering and small-world coefficients. Higher CSF p-tau 181 levels were related to lower betweenness centrality, path length and lambda coefficients (all p<0.01). Three-way interactions between p-tau181, amyloid status and CDR were found for path length, lambda and clustering (all p<0.05): Cognitively unimpaired amyloid-negative participants showed lower path length and lambda values with higher CSF p-tau181 levels. Amyloid-positive participants with impaired cognition demonstrated lower clustering coefficients in association to higher CSF p-tau181 levels. Our results suggest that alterations in gray matter network clustering coefficient is an early and specific event in AD.
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| 5. |
- Lövdén, Martin, 1972, et al.
(författare)
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No moderating influence of education on the association between changes in hippocampus volume and memory performance in aging
- 2023
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Contemporary accounts of factors that may modify the risk for age-related neurocognitive disorders highlight education and its contribution to a cognitive reserve. By this view, individuals with higher educational attainment should show weaker associations between changes in brain and cognition than individuals with lower educational attainment. We tested this prediction in longitudinal data on hippocampus volume and episodic memory from 708 middle-aged and older individuals using local structural equation modeling. This technique does not require categorization of years of education and does not constrain the shape of relationships, thereby maximizing the chances of revealing an effect of education on the hippocampus-memory association. The results showed that the data were plausible under the assumption that there was no influence of education on the association between change in episodic memory and change in hippocampus volume. Restricting the sample to individuals with elevated genetic risk for dementia (APOE ε4 carriers) did not change these results. We conclude that the influence of education on changes in episodic memory and hippocampus volume is inconsistent with predictions by the cognitive reserve theory.
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| 6. |
- Motovylyak, Alice, et al.
(författare)
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Age-related differences in white matter microstructure measured by advanced diffusion MRI in healthy older adults at risk for Alzheimer’s disease
- 2022
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique, which can detect more distinct microstructural features compared to conventional Diffusion Tensor Imaging (DTI). NODDI allows the signal to be divided into multiple water compartments and derive measures for orientation dispersion index (ODI), neurite density index (NDI) and volume fraction of isotropic diffusion compartment (FISO). This study aimed to investigate which diffusion metric—fractional anisotropy (FA), mean diffusivity (MD), NDI, ODI, or FISO—is most influenced by aging and reflects cognitive function in a population of healthy older adults at risk for Alzheimer’s disease (AD). Age was significantly associated with all but one diffusion parameters and regions of interest. NDI and MD in the cingulate region adjacent to the cingulate cortex showed a significant association with a composite measure of Executive Function and was proven to partially mediate the relationship between aging and Executive Function decline. These results suggest that both DTI and NODDI parameters are sensitive to age-related differences in white matter regions vulnerable to aging, particularly among older adults at risk for AD.
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| 7. |
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| 8. |
- Nyberg, Lars, 1966-, et al.
(författare)
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Longitudinal change-change associations of cognition with cortical thickness and surface area
- 2023
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Age-related changes in cortical volumes are well established but relatively few studies probed its constituents, surface area (SA) and thickness (TH). Here we analyzed 10-year, 3-waves longitudinal data from a large sample of healthy individuals (baseline age = 55–80). The findings showed marked age-related changes of SA in frontal, temporal, and parietal association cortices, and Bivariate Latent Change Score models revealed significant SA-associations with changes in speed of processing in both the 5- and 10-year models. The corresponding results for TH revealed a late onset of thinning and significant associations with reduced cognition in the 10-year model only. Taken together, our findings suggest that cortical surface area shrinks and impacts information-processing capacity gradually in aging, whereas cortical thinning only manifests and impacts fluid cognition in advanced aging.
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| 9. |
- Pedersen, Robin, et al.
(författare)
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Dopamine D1-signaling modulates maintenance of functional network segregation in aging
- 2023
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Past research has shown that as individuals age, there are decreases in within-network connectivity and increases in between-network connectivity, a pattern known as functional dedifferentiation. While the mechanisms behind reduced network segregation are not fully understood, evidence suggests that age-related differences in the dopamine (DA) system may play a key role. The DA D1-receptor (D1DR) is the most abundant and age-sensitive receptor subtype in the dopaminergic system, known to modulate synaptic activity and enhance the specificity of the neuronal signals. In this study from the DyNAMiC project (N = 180, 20-79y), we set out to investigate the interplay among age, functional connectivity, and dopamine D1DR availability. Using a novel application of multivariate Partial Least squares (PLS), we found that older age, and lower D1DR availability, were simultaneously associated with a pattern of decreased within-network and increased between-network connectivity. Individuals who expressed greater distinctiveness of large-scale networks exhibited more efficient working memory. In line with the maintenance hypotheses, we found that older individuals with greater D1DR in caudate exhibited less dedifferentiation of the connectome, and greater working memory, compared to their age-matched counterparts with less D1DR. These findings suggest that dopaminergic neurotransmission plays an important role in functional dedifferentiation in aging with consequences for working memory function at older age.
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