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| 2. |
- 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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| 3. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Effects of Baseline CSF alpha-Synuclein on Regional Brain Atrophy Rates in Healthy Elders, Mild Cognitive Impairment and Alzheimer's Disease
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cerebrospinal fluid (CSF) alpha-synuclein is reduced in synucleinopathies, including dementia with Lewy bodies, and some studies have found increased CSF alpha-synuclein in Alzheimer's disease (AD). No study has explored effects of CSF alpha-synuclein on brain atrophy. Here we tested if baseline CSF alpha-synuclein affects brain atrophy rates and if these effects vary across brain regions, and across the cognitive spectrum from healthy elders (NL), to patients with mild cognitive impairment (MCI) and AD. Methods: Baseline CSF alpha-synuclein measurements and longitudinal structural brain magnetic resonance imaging was performed in 74 NL, 118 MCI patients and 55 AD patients. Effects of baseline CSF alpha-synuclein on regional atrophy rates were tested in 1) four pre-hoc defined regions possibly associated with Lewy body and/or AD pathology (amygdala, caudate, hippocampus, brainstem), and 2) all available regions of interest. Differences across diagnoses were tested by assessing the interaction of CSF alpha-synuclein and diagnosis (testing NL versus MCI, and NL versus AD). Results: The effects of CSF alpha-synuclein on longitudinal atrophy rates were not significant after correction for multiple comparisons. There were tendencies for effects in AD in caudate (higher atrophy rates in subjects with higher CSF alpha-synuclein, P=0.046) and brainstem (higher atrophy rates in subjects with lower CSF alpha-synuclein, P=0.063). CSF alpha-synuclein had significantly different effects on atrophy rates in NL and AD in brainstem (P=0.037) and caudate (P=0.006). Discussion: With the possible exception of caudate and brainstem, the overall weak effects of CSF alpha-synuclein on atrophy rates in NL, MCI and AD argues against CSF alpha-synuclein as a biomarker related to longitudinal brain atrophy in these diagnostic groups. Any effects of CSF alpha-synuclein may be attenuated by possible simultaneous occurrence of AD-related neuronal injury and concomitant Lewy body pathology, which may elevate and reduce CSF alpha-synuclein levels, respectively.
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| 4. |
- 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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| 5. |
- Insel, P. S., et al.
(författare)
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Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease
- 2015
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 2:5, s. 534-547
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To find the combination of candidate biomarkers and cognitive endpoints to maximize statistical power and minimize cost of clinical trials of healthy elders at risk for cognitive decline due to Alzheimer's disease. Methods: Four-hundred and twelve cognitively normal participants were followed over 7 years. Nonlinear methods were used to estimate the longitudinal trajectories of several cognitive outcomes including delayed memory recall, executive function, processing speed, and several cognitive composites by subgroups selected on the basis of biomarkers, including APOE-epsilon 4 allele carriers, cerebrospinal fluid biomarkers (A beta(42), total tau, and phosphorylated tau), and those with small hippocampi. Results: Derived cognitive composites combining Alzheimer's Disease Assessment Scale (ADAS)-cog scores with additional delayed memory recall and executive function components captured decline more robustly across biomarker groups than any measure of a single cognitive domain or ADAS-cog alone. Substantial increases in power resulted when including only participants positive for three or more biomarkers in simulations of clinical trials. Interpretation: Clinical trial power may be improved by selecting participants on the basis of amyloid and neurodegeneration biomarkers and carefully tailoring primary cognitive endpoints to reflect the expected decline specific to these individuals.
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| 6. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Association of brain amyloid-beta with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment
- 2014
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137, s. 1550-1561
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Tidskriftsartikel (refereegranskat)abstract
- Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-beta pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-beta with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-beta accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-beta-negative controls and -positive subjects in different diagnostic groups, and if amyloid-beta had different associations with cerebral blood flow and grey matter volume. Global amyloid-beta load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-beta load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-beta-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-beta with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-beta being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-beta pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-beta pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.
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| 7. |
- Mattsson, Niklas, 1979, et al.
(författare)
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CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders
- 2013
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188 .- 2158-3188. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- β-amyloid (Ab) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1-42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Ab metabolism predict the development of Ab plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml1 after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Ab metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensinconverting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiveroperating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Ab metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Ab pathology at the earliest stages of AD, prior to widespread development of Aβ plaques. © 2013 Macmillan Publishers Limited All rights reserved.
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| 8. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Effects of cerebrospinal fluid proteins on brain atrophy rates in cognitively healthy older adults
- 2014
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 35:3, s. 614-622
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Tidskriftsartikel (refereegranskat)abstract
- Biomarkers associated with Alzheimer's disease (AD)-like brain atrophy in healthy individuals may identify mechanisms involved in early stage AD. Aside from cerebrospinal fluid (CSF) beta-amyloid42 (A beta 42) and tau, no studies have tested associations between CSF proteins and AD-like brain atrophy. We studied 90 healthy elders, who underwent lumbar puncture at baseline, and serial magnetic resonance imaging scans for up to 4 years. We tested statistical effects of baseline CSF proteins (N = 70 proteins related to A beta 42-metabolism, microglial activity, and synaptic/neuronal function) on atrophy rates in 7 AD-related regions. Besides the effects of A beta 42 and phosphorylated tau (P-tau) that were seen in several regions, novel CSF proteins were found to have effects in inferior and middle temporal cortex (including apolipoprotein CIII, apolipoprotein D, and apolipoprotein H). Several proteins (including S100 beta and matrix metalloproteinase-3) had effects that depended on the presence of brain A beta pathology, as measured by CSF A beta 42. Other proteins (including P-tau and apolipoprotein D) had effects even after adjusting for CSF A beta 42. The statistical effects in this exploratory study were mild and not significant after correction for multiple comparisons, but some of the identified proteins may be associated with brain atrophy in healthy persons. Proteins interacting with CSF A beta 42 may be related to A beta brain pathology, whereas proteins associated with atrophy even after adjusting for CSF A beta 42 may be related to A beta-independent mechanisms. (C) 2014 Elsevier Inc. All rights reserved.
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| 9. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Emerging β-amyloid pathology and accelerated cortical atrophy
- 2014
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 71:6, s. 725-734
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood. OBJECTIVE To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons. DESIGN, SETTING, AND PARTICIPANTS Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive. MAIN OUTCOMES AND MEASURES Group effects on regional gray matter volumes at baseline and over time, tested by linear mixed-effects models. RESULTS Baseline gray matter volumes were similar among the CN Aβ groups, but atrophy rates were increased in frontoparietal regions in the declining Aβ-negative and Aβ-positive groups and in amygdala and temporal regions in the Aβ-positive group. Aβ-positive patients with AD dementia had further increased atrophy rates in hippocampus and temporal and cingulate regions. CONCLUSIONS AND RELEVANCE Emerging Aβ pathology is coupled to increased frontoparietal (but not temporal) atrophy rates. Atrophy rates peak early in frontoparietal regions but accelerate in hippocampus, temporal, and cingulate regions as the disease progresses to dementia. Early-stage Aβ pathologymay have mild effects on local frontoparietal cortical integrity while effects in temporal regions appear later and accelerate, leading to the atrophy pattern typically seen in AD. © 2014 American Medical Association.
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