| 1. |
- Bainbridge, Wilma A., et al.
(author)
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Memorability of photographs in subjective cognitive decline and mild cognitive impairment : Implications for cognitive assessment
- 2019
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In: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 11, s. 610-618
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Journal article (peer-reviewed)abstract
- Introduction: Impaired long-term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently memorable. Methods: We conducted item-based analyses of long-term visual recognition memory. Three hundred ninety-four participants (healthy controls, subjective cognitive decline [SCD], and MCI) in the multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs. Results: We observed consistent memorability for images in healthy controls, SCD, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set. Discussion: Individuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.
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| 2. |
- Baumeister, Hannah, et al.
(author)
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A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
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In: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
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Journal article (peer-reviewed)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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| 3. |
- Jansen, Iris E, et al.
(author)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Journal article (peer-reviewed)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 4. |
- Kleineidam, Luca, et al.
(author)
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Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve
- 2022
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In: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 13
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Journal article (peer-reviewed)abstract
- Introduction: Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them. Methods: We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE). Results: Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM. Discussion: Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.
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| 5. |
- Leyhe, Thomas, et al.
(author)
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Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease
- 2009
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 16:3, s. 649-656
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Journal article (peer-reviewed)abstract
- Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). In experimental investigations, lithium induces brain-derived neurotrophic factor (BDNF). Recent studies have found a decrease of BDNF in the serum and brains of AD patients with potentially consecutive lack of neurotrophic support. We assessed the influence of a lithium treatment on BDNF serum concentration in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. In AD patients treated with lithium, a significant increase of BDNF serum levels, and additionally a significant decrease of ADAS-Cog sum scores in comparison to placebo-treated patients, were found. Diminution of cognitive impairment was inversely correlated with lithium serum concentration. Upregulation of BDNF might be part of a neuroprotective effect of lithium in AD patients. The results of the present investigation encourage performing studies with longer treatment phases to observe potential positive long-term effects of lithium in AD patients.
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| 6. |
- O'Bryant, Sid E, et al.
(author)
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Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research.
- 2015
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 11:5, s. 549-560
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Journal article (peer-reviewed)abstract
- The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross-validation across cohorts and laboratories.
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| 7. |
- Shen, Yong, et al.
(author)
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Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment.
- 2018
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In: Biological psychiatry. - : Elsevier BV. - 1873-2402 .- 1873-2402 .- 0006-3223. ; 83:5, s. 447-455
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Journal article (peer-reviewed)abstract
- Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects.Seventy-five patients with probable AD, 96 individuals with MCI, and 53 age-matched and sex-matched healthy control subjects were recruited from three independent international academic memory clinics and AD research expert centers. Plasma BACE1 activity was measured by a synthetic fluorescence substrate enzyme-linked immunosorbent assay. BACE1 protein expression was assessed by Western blotting using three different antibodies that recognize the epitopes of the N-terminus, C-terminus, and full-length BACE1.Compared with healthy control subjects, plasma BACE1 activity (Vmax) significantly increased by 53.2% in subjects with MCI and by 68.9% in patients with probable AD. Subjects with MCI who converted to probable AD dementia at follow-up examinations exhibited significantly higher BACE1 activity compared with cognitively stable MCI nonconverters and showed higher levels of BACE1 activity than patients with AD.Plasma BACE1 activity is significantly increased in MCI converters and patients with probable AD. The sensitivities and specificities of BACE1 activity for the patients were 84% and 88%, respectively. Our results indicate that plasma BACE1 activity may be a biomarker for AD risk and could predict progression from prodromal to probable AD dementia.
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| 8. |
- Straten, Guido, et al.
(author)
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Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimer΄s Disease
- 2011
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In: Current Alzheimer research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 8:8, s. 853-859
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Journal article (peer-reviewed)abstract
- Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer΄s disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebocontrolled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.
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