| 1. |
- Gonzales, M. M., et al.
(författare)
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Cortical Atrophy is Associated with Accelerated Cognitive Decline in Mild Cognitive Impairment with Subsyndromal Depression
- 2017
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Ingår i: American Journal of Geriatric Psychiatry. - : Elsevier BV. - 1064-7481. ; 25:9, s. 980-991
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate the association between cognitive decline and cortical atrophy in individuals with mild cognitive impairment (MCI) and chronic subsyndromal symptoms of depression (SSD) over a 4-year period. Design: Prospective cohort study. Setting: Multicenter, cwere observed for rate of decline on measures of attention, learning, and confrontation naming or for rate of atrophy in any other regions. Accelerated frontal lobe and anterior cingulate atrophy was associated with cognitive decline on measures of global cognition, information processing speed, and semantic fluency (all p < 0.05), but not memory. Conclusions: Individuals with chronic SSD may represent an MCI subgroup that is highly vulnerable to accelerated cognitive decline, an effect that may be governed by frontal lobe and anterior cingulate atrophy.linic-based. Participants: Within the Alzheimer's Disease Neuroimaging Initiative repository, the Neuropsychiatric Inventory was used to identify individuals with MCI and stable endorsement (SSD group N = 32) or no endorsement (non-SSD group N = 69) of depressive symptoms across time points. Measurements: Repeated measures of cognitive outcomes, cortical atrophy, and their associations were evaluated with mixed effects models adjusting for age, education, sex, and APOE genotype. Results: The SSD group demonstrated accelerated decline on measures of global cognition (Alzheimer Disease Assessment Scale; df = 421, t = 2.242, p = 0.025), memory (Wechsler Memory Scale-Revised Logical Memory II; df = 244, t = -2.525, p = 0.011), information processing speed (Trail Making Test Parts A [df = 421, t = 2.376, p = 0.018] and B [df = 421, t = 2.533, p = 0.012]), and semantic fluency (Category Fluency; df = 424, t = -2.418, p = 0.016), as well as accelerated frontal lobe (df = 341, t = -2.648, p = 0.008) and anterior cingulate (df = 341, t = -3.786, p < 0.001) atrophy. No group differences
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| 2. |
- Insel, Philip S., et al.
(författare)
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Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology
- 2016
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Ingår i: Neurology. - 0028-3878. ; 86:20, s. 1887-1896
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate. Methods: In 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ 42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression. Results: Rates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline. Conclusions: A considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ 42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline. © 2016 American Academy of Neurology.
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| 3. |
- Donohue, Michael C., et al.
(författare)
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Cross-validation of optimized composites for preclinical Alzheimer's disease
- 2017
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Ingår i: Alzheimer's and Dementia: Translational Research and Clinical Interventions. - : Wiley. - 2352-8737. ; 3:1, s. 123-129
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Tidskriftsartikel (refereegranskat)abstract
- Introduction We discuss optimization and validation of composite end points for presymptomatic Alzheimer's disease clinical trials. Optimized composites offer hope of substantial gains in statistical power or reduction in sample size. But there is tradeoff between optimization and face validity such that optimization should only be considered if there is a convincing rationale. As with statistically derived regions of interest in neuroimaging, validation on independent data sets is essential. Methods Using four data sets, we consider the optimized weighting of four components of a cognitive composite which includes measures of (1) global cognition, (2) semantic memory, (3) episodic memory, and (4) executive function. Weights are optimized to either discriminate amyloid positivity or maximize power to detect a treatment effect in an amyloid-positive population. We apply repeated 5 × 3-fold cross-validation to quantify the out-of-sample performance of optimized composite end points. Results We found the optimized weights varied greatly across the folds of the cross-validation with either optimization method. Both optimization methods tend to down-weight the measures of global cognition and executive function. However, when these optimized composites were applied to the validation sets, they did not provide consistent improvements in power. In fact, overall, the optimized composites performed worse than those without optimization. Discussion We find that component weight optimization does not yield valid improvements in sensitivity of this composite to detect treatment effects.
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| 4. |
- Insel, Philip S., et al.
(författare)
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Association of Sleep and β-Amyloid Pathology among Older Cognitively Unimpaired Adults
- 2021
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 4:7
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging β-amyloid (Aβ) pathology. Objective: To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults. Design, Setting, and Participants: In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had APOE genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021. Exposures: Self-reported daytime and nighttime sleep duration. Main Outcomes and Measures: Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio. Results: Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aβ positive). Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aβ standardized uptake value ratio (F1, 4419= 5.0; P =.03), a 0.009 reduction of medial orbitofrontal Aβ (F1, 4419= 17.4; P <.001), and a 0.011 reduction of anterior cingulate Aβ (F1, 4419= 15.9; P <.001). When restricting analyses to participants who tested Aβ negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aβ (F1,2910= 16.9; P <.001) and a 0.005 reduction of anterior cingulate Aβ (F1,2910= 7.6; P =.03). Daytime sleep was associated with a 0.013 increase of precuneus Aβ (F1,2910= 7.3; P =.03) and a 0.024 increase of posterior cingulate Aβ (F1,2910= 14.2; P =.001) in participants who tested Aβ negative. Conclusions and Relevance: In this cross-sectional study, the increased risk of Aβ deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aβ deposition. Daytime sleep may be associated with an increase in risk for early Aβ accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aβ accumulation. Treatments that improve sleep may reduce early Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.
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| 5. |
- Insel, Philip S., et al.
(författare)
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Cognitive and functional changes associated with Aβ pathology and the progression to mild cognitive impairment
- 2016
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 48, s. 172-181
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Tidskriftsartikel (refereegranskat)abstract
- Cognitively-normal people with evidence of β-amyloid (Aβ) pathology and subtle cognitive dysfunction are believed to be at high risk for progression to mild cognitive impairment due to Alzheimer's disease (AD). Clinical trials in later stages of AD typically include a coprimary endpoint to demonstrate efficacy on both cognitive and functional assessments. Recent trials focus on cognitively-normal people, but functional decline has not been explored for trial designs in this group. The goal of this study was therefore to characterize cognitive and functional decline in (1) cognitively-normal people converting to mild cognitive impairment (MCI) and (2) cognitively-normal β-amyloid-positive (Aβ+) people. Specifically, we sought to identify and compare the cognitive and functional assessments and their weighted combinations that maximize the longitudinal decline specific to these 2 groups. We studied 68 people who converted from normal cognition to MCI and 70 nonconverters, as well as 137 Aβ+ and 210 β-amyloid-negative cognitively-normal people. We used bootstrap aggregation and cross-validated mixed-models to estimate the distribution of weights applied to cognitive and functional outcomes to form composites. We also evaluated best subset optimization. Using optimized composites, we estimated statistical power for a variety of clinical trial scenarios. Overall, 55.4% of cognitively-normal to MCI converters were Aβ+. Large gains in power estimates were obtained when requiring participants to have both subtle cognitive dysfunction and Aβ pathology compared with requiring Aβ pathology alone. Additional power resulted when including functional as well as cognitive outcomes as part of the composite. Composites formed by applying equal weights to all measures provided the highest estimates of cross-validated power, although similar to both continuous weight optimization and best subset optimization. Using a composite to detect a 30% slowing of decline, 80% power was obtained for predicted Aβ+ converters with 375 completers/arm for a 30-month trial using a combination of cognitive/ functional measures. In the Aβ+ group, power to approach levels suitable for a phase III clinical trial would require considerably larger sample sizes. Composites incorporating both cognitive and functional measures may substantially increase the power of a trial in a preclinical (Aβ+) AD population with subtle evidence of cognitive dysfunction.
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| 6. |
- Baumeister, Hannah, et al.
(författare)
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A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
- 2024
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
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Tidskriftsartikel (refereegranskat)abstract
- Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.
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| 7. |
- Berron, David, et al.
(författare)
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Early stages of tau pathology and its associations with functional connectivity, atrophy and memory
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2771-2783
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Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer's disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-β- cognitively unimpaired, 81 amyloid-β+ cognitively unimpaired and 87 amyloid-β+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.
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| 8. |
- Cullen, Nicholas C., et al.
(författare)
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Comparing progression biomarkers in clinical trials of early Alzheimer's disease
- 2020
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 7:9, s. 1661-1673
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the statistical power of plasma, imaging, and cognition biomarkers as Alzheimer's disease (AD) clinical trial outcome measures. Methods: Plasma neurofilament light, structural magnetic resonance imaging, and cognition were measured longitudinally in the Alzheimer's Disease Neuroimaging Initiative (ADNI) in control (amyloid PET or CSF A beta 42 negative [A beta-] with Clinical Dementia Rating scale [CDR] = 0; n = 330), preclinical AD (A beta + with CDR = 0; n = 218) and mild AD (A beta + with CDR = 0.5-1; n = 697) individuals. A statistical power analysis was performed across biomarkers and groups based on longitudinal mixed effects modeling and using several different clinical trial designs. Results: For a 30-month trial of preclinical AD, both the temporal composite and hippocampal volumes were superior to plasma neurofilament light and cognition. For an 18-month trial of mild AD, hippocampal volume was superior to all other biomarkers. Plasma neurofilament light became more effective with increased trial duration or sampling frequency. Imaging biomarkers were characterized by high slope and low within-subject variability, while plasma neurofilament light and cognition were characterized by higher within-subject variability. Interpretation: MRI measures had properties that made them preferable to cognition and pNFL as outcome measures in clinical trials of early AD, regardless of cognitive status. However, pNfL and cognition can still be effective depending on inclusion criteria, sampling frequency, and response to therapy. Future trials will help to understand how sensitive pNfL and MRI are to detect downstream effects on neurodegeneration of drugs targeting amyloid and tau pathology in AD.
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| 9. |
- Gonzales, Mitzi M., et al.
(författare)
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Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment
- 2018
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Ingår i: International Journal of Geriatric Psychiatry. - : Wiley. - 0885-6230 .- 1099-1166. ; 33:10, s. 1305-1311
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate the association between chronic subsyndromal symptoms of depression (SSD), cerebrospinal fluid (CSF) biomarkers, and neuropsychological performance in individuals with mild cognitive impairment (MCI). Methods: Participants included 238 older adults diagnosed with MCI from the Alzheimer's Disease Neuroimaging Initiative repository with cognitive and CSF amyloid beta (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) data. The Neuropsychiatric Inventory identified individuals with chronic endorsement (SSD group N = 80) or no endorsement (non-SSD group N = 158) of depressive symptoms across timepoints. CSF biomarker and cognitive performance were evaluated with linear regression models adjusting for age, education, gender, APOE genotype, global cognitive status, and SSD group. Results: As compared to the non-SSD group, the SSD group displayed lower CSF Aβ1–42 levels (β = −24.293, S.E. = 6.345, P < 0.001). No group differences were observed for CSF t-tau (P = 0.497) or p-tau levels (P = 0.392). Lower CSF Aβ1–42 levels were associated with poorer performance on learning (β = 0.041, S.E. = 0.018, P = 0.021) and memory (β = −0.012, S.E. = 0.005, P = 0.031) measures, whereas higher CSF t-tau levels were associated with poorer performance on measures of global cognition (β = 0.022, S.E = 0.008, P = 0.007) and language (β = −0.010, S.E = 0.004, P = 0.019). SSD was independently associated with diminished global cognition, learning and memory, language, and executive function performance over and above the effects of CSF biomarkers (all P < 0.05). Conclusions: MCI participants with SSD displayed diminished CSF Aβ1–42 levels but did not differ from non-SSD controls in CSF tau levels. Additionally, CSF biomarkers and SSD independently accounted for variance in cognitive performance, suggesting that these factors may uniquely confer cognitive risk in MCI.
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| 10. |
- Hansson, Oskar, et al.
(författare)
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The genetic regulation of protein expression in cerebrospinal fluid
- 2023
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10−10, 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome.
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