| 1. |
- 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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| 2. |
- Insel, Philip S., et al.
(författare)
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Assessing risk for preclinical β-amyloid pathology with APOE, cognitive, and demographic information
- 2016
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 4, s. 76-84
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Clinical trials in Alzheimer's disease are aimed at early stages of disease, including preclinical Alzheimer's disease. The high cost and time required to screen large numbers of participants for Aβ pathology impede the development of novel drugs. This study's objective was to evaluate the extent to which inexpensive and easily obtainable information can reduce the number of screen failures by increasing the proportion of Aβ+ participants identified for screening. Methods We used random forest models to evaluate the positive predictive value of demographics, APOE, and longitudinal cognitive rates in the prediction of amyloid pathology, measured by florbetapir PET or cerebrospinal fluid. Results Predicting Aβ positivity with demographic, APOE, and cognitive information yielded a positive predictive value estimate of 0.65 (95% CI, 0.50–0.96), nearly a 60% increase over the reference Aβ+ prevalence in the cohort of 0.41. Conclusions By incorporating this procedure, clinical trial screening costs of 7500 USD per participant may be reduced by nearly 7 million USD total.
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| 3. |
- 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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| 4. |
- Insel, Philip S., et al.
(författare)
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Time to amyloid positivity and preclinical changes in brain metabolism, atrophy, and cognition : Evidence for emerging amyloid pathology in alzheimer's disease
- 2017
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 11:MAY
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition. Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines. Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity. Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range.
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| 5. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.
- 2015
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 138:3, s. 772-783
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Tidskriftsartikel (refereegranskat)abstract
- Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that cerebrospinal fluid and positron emission tomography amyloid-β provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-β but normal positron emission tomography amyloid-β, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease progression.
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| 6. |
- Mattsson, Niklas, et al.
(författare)
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Plasma tau in Alzheimer disease
- 2016
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 87:17, s. 1827-1835
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To test whether plasma tau is altered in Alzheimer disease (AD) and whether it is related to changes in cognition, CSF biomarkers of AD pathology (including β-amyloid [Aβ] and tau), brain atrophy, and brain metabolism. Methods: This was a study of plasma tau in prospectively followed patients with AD (n 179), patients with mild cognitive impairment (n 195), and cognitive healthy controls (n 189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied patients with AD (n 61), mild cognitive impairment (n 212), and subjective cognitive decline (n 174) and controls (n 274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were studied. Associations were tested between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18 fluorodeoxyglucose-PET, and cognition. Results: Higher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ 42, but the correlations were weak and differed between ADNI and BioFINDER. Longitudinal analysis in ADNI showed significant associations between plasma tau and worse cognition, more atrophy, and more hypometabolism during follow-up. Conclusions: Plasma tau partly reflects AD pathology, but the overlap between normal aging and AD is large, especially in patients without dementia. Despite group-level differences, these results do not support plasma tau as an AD biomarker in individual people. Future studies may test longitudinal plasma tau measurements in AD.
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| 7. |
- Portelius, Erik, 1977, et al.
(författare)
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Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease.
- 2015
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 138, s. 3373-3385
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic dysfunction is linked to cognitive symptoms in Alzheimer's disease. Thus, measurement of synapse proteins in cerebrospinal fluid may be useful biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic protein neurogranin are increased in Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid neurogranin to predict cognitive decline and brain injury in the Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having Alzheimer's disease with dementia (n = 95) or mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable mild cognitive impairment) and those who progressed to Alzheimer's disease dementia during follow-up (progressive mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid neurogranin levels and baseline and longitudinal cognitive impairment, brain atrophy and glucose metabolism within each diagnostic group. Cerebrospinal fluid neurogranin was increased in patients with Alzheimer's disease dementia (P < 0.001), progressive mild cognitive impairment (P < 0.001) and stable mild cognitive impairment (P < 0.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P < 0.05) compared with stable mild cognitive impairment. In the mild cognitive impairment group, high baseline cerebrospinal fluid neurogranin levels predicted cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.
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