| 1. |
- Alafuzoff, Irina, et al.
(författare)
-
Mixed Brain Pathology Is the Most Common Cause of Cognitive Impairment in the Elderly
- 2020
-
Ingår i: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 78:1, s. 453-465
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer's disease neuropathologic change (ADNC).Objective: The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney.Methods: 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry.Results: Hyperphosphorylated tau (HP tau) was seen in 99%, amyloid-beta (A beta) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and alpha-synuclein (alpha S) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPt increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology.Conclusion: In most (66%) subjects with CI, the cause of impairment was "mixed pathology", i.e., ADNC combined with TDP43, alpha S, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DMand CaVD, are risk factors for CI but not related to ADNC.
|
|
| 2. |
- Almkvist, Ove, et al.
(författare)
-
Subcortical and Cortical Regions of Amyloid-β Pathology Measured by C-11-PiB PET Are Differentially Associated with Cognitive Functions and Stages of Disease in Memory Clinic Patients
- 2021
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 81:4, s. 1613-1624
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The effect of regional brain amyloid-beta (A beta) pathology on specific cognitive functions is incompletely known.Objective: The relationship between A beta and cognitive functions was investigated in this cross-sectional multicenter study of memory clinic patients.Methods: The participants were patients diagnosed with Alzheimer's disease (AD, n = 83), mild cognitive impairment (MCI, n = 60), and healthy controls (HC, n = 32), who had been scanned by C-11-PiB PET in 13 brain regions of both hemispheres and who had been assessed by cognitive tests covering seven domains.Results: Hierarchic multiple regression analyses were performed on each cognitive test as dependent variable, controlling for demographic characteristics and APOE status (block 1) and PiB measures in 13 brain regions (block 2) as independent variables. The model was highly significant for each cognitive test and most strongly for tests of episodic memory (learning and retention) versus PiB in putamen, visuospatially demanding tests (processing and retention) versus the occipital lobe, semantic fluency versus the parietal lobe, attention versus posterior gyrus cinguli, and executive function versus nucleus accumbens. In addition, education had a positively and APOE status a negatively significant effect on cognitive tests.Conclusion: Five subcortical and cortical regions with A beta pathology are differentially associated with cognitive functions and stages of disease in memory clinic patients.
|
|
| 3. |
- Axelsson, Elin, et al.
(författare)
-
Patients with the Subcortical Small Vessel Type of Dementia Have Disturbed Cardiometabolic Risk Profile
- 2020
-
Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 73:4, s. 1373-1383
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Population-based studies have shown that cardiometabolic status is associated with the amount of white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI). However, little is known of cardiometabolic risk factors in the subcortical small vessel type of dementia (SSVD), in which WMHs are one of the most prominent manifestations. Objective: To determine whether the profile of cardiometabolic risk factors differed between SSVD, Alzheimer's disease (AD), mixed dementia (combined AD and SSVD), and healthy controls. Methods: This was a mono-center, cross-sectional study of SSVD (n = 40), AD (n = 113), mixed dementia (n = 62), and healthy controls (n = 94). In the statistical analyses, we adjusted for covariates using ANCOVA and binary logistic regression. Results: The prevalence of hypertension was increased in SSVD and mixed dementia (p < 0.001 and p < 0.05 versus controls, respectively). Diabetes was more prevalent in SSVD patients, and body mass index was lower in AD and mixed dementia, compared to the controls (all p < 0.05). Serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) were reduced in the SSVD group (both p < 0.05 versus control). These differences remained after adjustment for covariates. In the SSVD group, Trail Making Test A score correlated positively with systolic blood pressure, mean arterial pressure, and pulse pressure. Conclusion: All dementia groups had an altered cardiometabolic risk profile compared to the controls. The SSVD patients showed increased prevalence of hypertension and diabetes, and in line with previous population-based data, TC and LDL-C in serum were reduced.
|
|
| 4. |
- Beam, Christopher R., et al.
(författare)
-
Estimating Likelihood of Dementia in the Absence of Diagnostic Data : A Latent Dementia Index in 10 Genetically Informed Studies
- 2022
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:3, s. 1187-1201
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Epidemiological research on dementia is hampered by differences across studies in how dementia is classified, especially where clinical diagnoses of dementia may not be available. OBJECTIVE: We apply structural equation modeling to estimate dementia likelihood across heterogeneous samples within a multi-study consortium and use the twin design of the sample to validate the results. METHODS: Using 10 twin studies, we implement a latent variable approach that aligns different tests available in each study to assess cognitive, memory, and functional ability. The model separates general cognitive ability from components indicative of dementia. We examine the validity of this continuous latent dementia index (LDI). We then identify cut-off points along the LDI distributions in each study and align them across studies to distinguish individuals with and without probable dementia. Finally, we validate the LDI by determining its heritability and estimating genetic and environmental correlations between the LDI and clinically diagnosed dementia where available. RESULTS: Results indicate that coordinated estimation of LDI across 10 studies has validity against clinically diagnosed dementia. The LDI can be fit to heterogeneous sets of memory, other cognitive, and functional ability variables to extract a score reflective of likelihood of dementia that can be interpreted similarly across studies despite diverse study designs and sampling characteristics. Finally, the same genetic sources of variance strongly contribute to both the LDI and clinical diagnosis. CONCLUSION: This latent dementia indicator approach may serve as a model for other research consortia confronted with similar data integration challenges.
|
|
| 5. |
- Boström, Gustaf, et al.
(författare)
-
Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid
- 2021
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 81:2, s. 629-640
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.
|
|
| 6. |
- Chatterjee, P., et al.
(författare)
-
Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-beta Load
- 2020
-
Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 76:1, s. 291-301
-
Tidskriftsartikel (refereegranskat)abstract
- Background/Objective: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-beta load (NAL). Methods: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)<1.35 was classified as low NAL (n = 65) and >= 1.35 (n = 35) was classified as high NAL. Results: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOE epsilon 4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma A beta(42/40) ratio (AUC = 0.829). Conclusion: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.
|
|
| 7. |
- Classon, Elisabet, et al.
(författare)
-
Montreal Cognitive Assessment: Normative Data for Cognitively Healthy Swedish 80-to 94-Year-Olds
- 2022
-
Ingår i: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 87:3, s. 1335-1344
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The Montreal Cognitive Assessment (MoCA) is sensitive to cognitive impairment; however, it is also sensitive to demographic and socio-cultural factors. This necessitates reliable sub-population norms, but these are often lacking for older adults. Objective: To present demographically adjusted regression-based MoCA norms for cognitively healthy Swedish older adults. Methods: A pseudo-random sample of community-dwelling 80- to 94-year-olds, stratified by age and gender, was invited to the study. Initial telephone interviews and medical records searches (n = 218) were conducted to screen for cognitive impairment. N= 181 eligible participants were administered a protocol including the Swedish version of the MoCA and assessments of global cognition (Mini-Mental State Examination, MMSE) and depression (Patient Health Questionnaire-9, PHQ-9). Individuals scoring in the range of possible cognitive impairment on the MMSE or more than mild depression on the PHQ-9 were excluded (n = 23); three discontinued the test-session. Results: Norms were derived from the remaining n = 158. They were evenly distributed by gender, on average 85 years old, and with a mean education of 11 years. MoCA scores were independently influenced by age and education, together explaining 17.2% of the total variance. Higher age and lower education were associated with lower performance and 46% performed below the original cut-off (< 26/30). Conclusion: The negative impact of increasing age on MoCA performance continues linearly into the nineties in normal aging. Demographic factors should be considered when interpreting MoCA performance and a tool for computing demographically corrected standard scores is provided.
|
|
| 8. |
- Cummings, J., et al.
(författare)
-
Cognitive Effects of the BET Protein Inhibitor Apabetalone: A Prespecified Montreal Cognitive Assessment Analysis Nested in the BETonMACE Randomized Controlled Trial
- 2021
-
Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 83:4, s. 1703-1715
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer's disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic "readers" that may distort normal gene expression and contribute to chronic disorders. Objective: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). Methods: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score >= 26 (normal performance), MoCA score 25-22 (mild cognitive impairment), and MoCA score <= 21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. Results: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of <= 21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). Conclusion: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.
|
|
| 9. |
- Dentoni, Giacomo, et al.
(författare)
-
Mitochondrial Alterations in Neurons Derived from the Murine AppNL-F Knock-In Model of Alzheimer's Disease
- 2022
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:2, s. 565-583
-
Tidskriftsartikel (refereegranskat)abstract
- Background:Alzheimer’s disease (AD) research has relied on mouse models overexpressing human mutant A βPP; however, newer generation knock-in models allow for physiological expression of amyloid-β protein precursor (AβPP) containing familial AD mutations where murine AβPP is edited with a humanized amyloid-β (Aβ) sequence. The AppNL-F mouse model has shown substantial similarities to AD brains developing late onset cognitive impairment.Objective:In this study, we aimed to characterize mature primary cortical neurons derived from homozygous AppNL-F embryos, especially to identify early mitochondrial alterations in this model.Methods:Primary cultures of AppNL-F neurons kept in culture for 12–15 days were used to measure Aβ levels, secretase activity, mitochondrial functions, mitochondrial-ER contacts, synaptic function, and cell death.Results:We detected higher levels of Aβ42 released from AppNL-F neurons as compared to wild-type neurons. AppNL-F neurons, also displayed an increased Aβ42/Aβ40 ratio, similar to adult AppNL-F mouse brain. Interestingly, we found an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL-F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which may account for upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function.Conclusion:We show that widespread mitochondrial alterations can be detected in AppNL-F neurons in vitro, where amyloid plaque deposition does not occur, suggesting soluble and oligomeric Aβ-species being responsible for these alterations.
|
|
| 10. |
- Edlund, Anna K., 1983-, et al.
(författare)
-
Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ɛ3/ɛ4 Carriers
- 2021
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 81:1, s. 339-354
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain.Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores.Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI.Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores.Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.
|
|
