| 1. |
- Capogna, Elettra, et al.
(författare)
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Subtypes of brain change in aging and their associations with cognition and Alzheimer's disease biomarkers.
- 2024
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Ingår i: bioRxiv : the preprint server for biology.
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Tidskriftsartikel (refereegranskat)abstract
- Structural brain changes underly cognitive changes in older age and contribute to inter-individual variability in cognition. Here, we assessed how changes in cortical thickness, surface area, and subcortical volume, are related to cognitive change in cognitively unimpaired older adults using structural magnetic resonance imaging (MRI) data-driven clustering. Specifically, we tested (1) which brain structural changes over time predict cognitive change in older age (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers phosphorylated tau (p-tau) and amyloid-β (Aβ42), and (3) the degree of overlap between clusters derived from different structural features. In total 1899 cognitively healthy older adults (50 - 93 years) were followed up to 16 years with neuropsychological and structural MRI assessments, a subsample of which (n = 612) had CSF p-tau and Aβ42 measurements. We applied Monte-Carlo Reference-based Consensus clustering to identify subgroups of older adults based on structural brain change patterns over time. Four clusters for each brain feature were identified, representing the degree of longitudinal brain decline. Each brain feature provided a unique contribution to brain aging as clusters were largely independent across modalities. Cognitive change and baseline cognition were best predicted by cortical area change, whereas higher levels of p-tau and Aβ42 were associated with changes in subcortical volume. These results provide insights into the link between changes in brain morphology and cognition, which may translate to a better understanding of different aging trajectories.
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| 2. |
- Fjell, Anders Martin, et al.
(författare)
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Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy.
- 2018
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Ingår i: Cerebral cortex (New York, N.Y. : 1991). - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 28:8, s. 2775-2785
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Tidskriftsartikel (refereegranskat)abstract
- Sleep problems relate to brain changes in aging and disease, but the mechanisms are unknown. Studies suggest a relationship between β-amyloid (Aβ) accumulation and sleep, which is likely augmented by interactions with multiple variables. Here, we tested how different cerebrospinal fluid (CSF) biomarkers for brain pathophysiology, brain atrophy, memory function, and depressive symptoms predicted self-reported sleep patterns in 91 cognitively healthy older adults over a 3-year period. The results showed that CSF levels of total- and phosphorylated (P) tau, and YKL-40-a marker of neuroinflammation/astroglial activation-predicted poor sleep in Aβ positive older adults. Interestingly, although brain atrophy was strongly predictive of poor sleep, the relationships between CSF biomarkers and sleep were completely independent of atrophy. A joint analysis showed that unique variance in sleep was explained by P-tau and the P-tau × Aβ interaction, memory function, depressive symptoms, and brain atrophy. The results demonstrate that sleep relates to a range of different pathophysiological processes, underscoring the importance of understanding its impact on neurocognitive changes in aging and people with increased risk of Alzheimer's disease.
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| 3. |
- Fjell, Anders M., et al.
(författare)
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Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium
- 2021
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Ingår i: Cerebral Cortex. - : Oxford University Press. - 1047-3211 .- 1460-2199. ; 31:4, s. 1953-1969
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Tidskriftsartikel (refereegranskat)abstract
- We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.
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| 4. |
- Fjell, Anders M., et al.
(författare)
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Self-reported sleep relates to hippocampal atrophy across the adult lifespan : results from the Lifebrain consortium
- 2020
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Ingår i: Sleep. - : Oxford University Press. - 0161-8105 .- 1550-9109. ; 43:5
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Poor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan.Methods: Self-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18–90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants for whom longitudinal MRIs were available, followed up to 11 years with a mean interval of 3.3 years. Cross-sectional analyses were repeated in a sample of 21,390 participants from the UK Biobank.Results: No cross-sectional sleep—hippocampal volume relationships were found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing 0.22% greater annual loss than low scorers. The relationship between sleep and hippocampal atrophy did not vary across age. Simulations showed that the observed longitudinal effects were too small to be detected as age-interactions in the cross-sectional analyses.Conclusions: Worse self-reported sleep is associated with higher rates of hippocampal volume decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation.
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| 5. |
- Gorbach, Tetiana, 1991-, et al.
(författare)
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Longitudinal association between hippocampus atrophy and episodic-memory decline in non-demented APOE ε4 carriers
- 2020
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Ingår i: Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. - : John Wiley & Sons. - 2352-8729. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for Alzheimer's disease (AD), accelerated cognitive aging, and hippocampal atrophy, but its influence on the association between hippocampus atrophy and episodic-memory decline in non-demented individuals remains unclear.Methods: We analyzed longitudinal (two to six observations) magnetic resonance imaging (MRI)–derived hippocampal volumes and episodic memory from 748 individuals (55 to 90 years at baseline, 50% female) from the European Lifebrain consortium.Results: The change-change association for hippocampal volume and memory was significant only in ε4 carriers (N = 173, r = 0.21, P = .007; non-carriers: N = 467, r = 0.073,P = .117). The linear relationship was significantly steeper for the carriers [t(629) =2.4, P = .013]. A similar trend toward a stronger change-change relation for carriers was seen in a subsample with more than two assessments.Discussion: These findings provide evidence for a difference in hippocampus-memory association between ε4 carriers and non-carriers, thus highlighting how genetic factors modulate the translation of the AD-related pathophysiological cascade into cognitive deficits.
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| 6. |
- Halaas, Nathalie Bodd, et al.
(författare)
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Cerebrospinal Fluid Concentration of Neurogranin in Hip Fracture Patients with Delirium.
- 2021
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Ingår i: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 81:2, s. 667-677
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Tidskriftsartikel (refereegranskat)abstract
- Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer's disease (AD), likely reflecting synaptic dysfunction and/or degeneration.To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients.The cohort included hip fracture patients with (n=70) and without delirium (n=58), CUA undergoing elective surgery (n=127), and AD patients (n=46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers.No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p=0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p=0.001) and CUA (p=0.035) in age-adjusted sensitivity analyses.The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium.
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| 7. |
- Halaas, Nathalie Bodd, et al.
(författare)
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CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults.
- 2020
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Ingår i: Cerebral cortex (New York, N.Y. : 1991). - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 30:4, s. 2295-2306
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Tidskriftsartikel (refereegranskat)abstract
- Neuroinflammation may be a key factor in brain atrophy in aging and age-related neurodegenerative disease. The objective of this study was to test the association between microglial expression of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2), as a measure of neuroinflammation, and brain atrophy in cognitively unimpaired older adults. Brain magnetic resonance imagings (MRIs) and cerebrospinal fluid (CSF) sTREM2, total tau (t-tau), phosphorylated181 tau (p-tau), and Aβ42 were analyzed in 115 cognitively unimpaired older adults, classified according to the A/T/(N)-framework. MRIs were repeated after 2 (n=95) and 4 (n=62) years. High baseline sTREM2 was associated with accelerated cortical thinning in the temporal cortex of the left hemisphere, as well as bilateral hippocampal atrophy, independently of age, Aβ42, and tau. sTREM2-related atrophy only marginally increased with biomarker positivity across the AD continuum (A-T- #x2292; A+T- #x2292; A+T+) but was significantly stronger in participants with a high level of p-tau (T+). sTREM2-related cortical thinning correlated significantly with areas of high microglial-specific gene expression in the Allen Human Brain Atlas. In conclusion, increased CSF sTREM2 was associated with accelerated cortical and hippocampal atrophy in cognitively unimpaired older participants, particularly in individuals with tau pathology. This suggests a link between neuroinflammation, neurodegeneration, and amyloid-independent tauopathy.
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| 8. |
- Halaas, Nathalie Bodd, et al.
(författare)
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Neurofilament Light in Serum and Cerebrospinal Fluid of Hip Fracture Patients with Delirium.
- 2018
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 46:5-6, s. 346-357
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Tidskriftsartikel (refereegranskat)abstract
- Delirium is associated with new-onset dementia, suggesting that delirium pathophysiology involves neuronal injury. Neurofilament light (NFL) is a sensitive biomarker for neuroaxonal injury.NFL was measured in cerebrospinal fluid (CSF) (n = 130), preoperative serum (n = 192), and postoperative serum (n = 280) in hip fracture patients, and in CSF (n = 123) and preoperative serum (n = 134) in cognitively normal older adults undergoing elective surgery. Delirium was diagnosed with the Confusion Assessment Method.Median serum NFL (pg/mL) was elevated in delirium in hip fracture patients (94 vs. 54 pre- and 135 vs. 92 postoperatively, both p < 0.001). Median CSF NFL tended to be higher in hip fracture patients with delirium (1,804 vs. 1,636, p = 0.074). Serum and CSF NFL were positively correlated (ρ = 0.56, p < 0.001).Our findings support an association between neuroaxonal injury and delirium. The correlation between serum and CSF NFL supports the use of NFL as a blood biomarker in future delirium studies.
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| 9. |
- Idland, Ane-Victoria, et al.
(författare)
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CSF neurofilament light levels predict hippocampal atrophy in cognitively healthy older adults.
- 2017
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 49, s. 138-144
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) neurofilament light (NFL) is a marker of axonal degeneration. We tested whether CSF NFL levels predict hippocampal atrophy rate in cognitively healthy older adults independently of the established CSF Alzheimer's disease (AD) biomarkers, β-amyloid 1-42, and phosphorylated tau (P-tau). We included 144 participants in a 2-year longitudinal study with baseline CSF measures and2 magnetic resonance images. Eighty-eight participants had full data available. A subgroup of 36participants with very low AD risk was also studied. NFL predicted hippocampal atrophy rate independently of age, β-amyloid 1-42, and P-tau. Including NFL, P-tau, and age in the same model, higher NFL and lower P-tau predicted higher hippocampal atrophy (R(2)= 0.20, NFL: β=-0.34; p= 0.003; P-tau: β= 0.27; p= 0.009). The results were upheld in the participants with very low AD risk. NFL predicted neurodegeneration in older adults with very low AD probability. We suggest that factors previously shown to be important for brain degeneration in mild cognitive impairment may also impact changes innormal aging, demonstrating that NFL is likely to indicate AD-independent, age-expected neurodegeneration.
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| 10. |
- Idland, Ane Victoria, et al.
(författare)
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Preclinical amyloid-β and axonal degeneration pathology in delirium
- 2016
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 55:1, s. 371-379
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Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical relevance of brain β-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues. Objective: To determine whether the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia. Methods: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aβ42, T-tau, and P-tau were analyzed. Results: In patients without dementia, we found lower CSF Aβ42 levels (median, 310ng/L versus 489ng/L, p=0.006), higher T-tau levels (median, 505ng/L versus 351ng/L, p=0.02), but no change in P-tau in patients who developed delirium (n=16) compared to those who remained lucid (n=49). Delirious patients also had lower ratios of Aβ42 to T-tau (p<0.001) and P-tau (p=0.001) relative to those without delirium. CSF Aβ42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (n=54) and without delirium (n=10). Conclusion: The reduction in CSF Aβ42, indicating β-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology.
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| 11. |
- Rongve, Arvid, et al.
(författare)
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GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10 −8 ). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10 −6 . We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.
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| 12. |
- Sajjad, Muhammad Umar, et al.
(författare)
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Cerebrospinal Fluid Levels of Interleukin-8 in Delirium, Dementia, and Cognitively Healthy Patients.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 73:4, s. 1363-1372
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Tidskriftsartikel (refereegranskat)abstract
- Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known.The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium.In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer's disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay.Hip fracture patients had significantly higher IL-8 levels (p<0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (p=0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (p=0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (p=0.002) in delirium patients with depression. Both TNF-α and IL-1β were undetected in most patients.Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels.
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| 13. |
- Sala-Llonch, Roser, et al.
(författare)
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Inflammation, Amyloid, and Atrophy in The Aging Brain: Relationships with Longitudinal Changes in Cognition.
- 2017
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 58:3, s. 829-840
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid deposition occurs in aging, even in individuals free from cognitive symptoms, and is often interpreted as preclinical Alzheimer's disease (AD) pathophysiology. YKL-40 is a marker of neuroinflammation, being increased in AD, and hypothesized to interact with amyloid-β (Aβ) in causing cognitive decline early in the cascade of AD pathophysiology. Whether and how Aβ and YKL-40 affect brain and cognitive changes in cognitively healthy older adults is still unknown. We studied 89 participants (mean age: 73.1 years) with cerebrospinal fluid samples at baseline, and both MRI and cognitive assessments from two time-points separated by two years. We tested how baseline levels of Aβ42 and YKL-40 correlated with changes in cortical thickness and cognition. Thickness change correlated with Aβ42 only in Aβ42+ participants (<600 pg/mL, n=27) in the left motor and premotor cortices. Aβ42 was unrelated to cognitive change. Increased YKL-40 was associated with less preservation of scores on the animal naming test in the total sample (r=-0.28, p=0.012) and less preservation of a score reflecting global cognitive function for Aβ42+ participants (r=-0.58, p=0.004). Our results suggest a role for inflammation in brain atrophy and cognitive changes in cognitively normal older adults, which partly depended on Aβ accumulation.
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| 14. |
- Watne, Leiv Otto, et al.
(författare)
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Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip fracture patients.
- 2023
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Ingår i: The Journal of clinical investigation. - 1558-8238. ; 133:2
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Tidskriftsartikel (refereegranskat)abstract
- The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanism underlying delirium, particularly in relation to the KP, remain elusive.We undertook a multi-center observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and one-year mortality.In delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA, OR 2.26 [1.78, 2.87], p<0.001) to be increased, as well as increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL, β 0.43, p<0.001) and was a strong predictor of one-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, p<0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.Our data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP, and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.Norwegian Health Association and the South-Eastern Norway Regional Health Authorities.
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