| 1. |
- Jansen, Iris E, et al.
(författare)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Bruno, Davide, et al.
(författare)
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A study on the specificity of the association between hippocampal volume and delayed primacy performance in cognitively intact elderly individuals.
- 2015
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Ingår i: Neuropsychologia. - : Elsevier BV. - 1873-3514 .- 0028-3932. ; 69, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Delayed recall at the primacy position (first few items on a list) has been shown to predict cognitive decline in cognitively intact elderly participants, with poorer delayed primacy performance associated with more pronounced generalized cognitive decline during follow-up. We have previously suggested that this association is due to delayed primacy performance indexing memory consolidation, which in turn is thought to depend upon hippocampal function. Here, we test the hypothesis that hippocampal size is associated with delayed primacy performance in cognitively intact elderly individuals. Data were analyzed from a group (N=81) of cognitively intact participants, aged 60 or above. Serial position performance was measured with the Buschke selective reminding test (BSRT). Hippocampal size was automatically measured via MRI, and unbiased voxel-based analyses were also conducted to explore further regional specificity of memory performance. We conducted regression analyses of hippocampus volumes on serial position performance; other predictors included age, family history of Alzheimer's disease (AD), APOE ε4 status, education, and total intracranial volume. Our results collectively suggest that there is a preferential association between hippocampal volume and delayed primacy performance. These findings are consistent with the hypothesis that delayed primacy consolidation is associated with hippocampal size, and shed light on the relationship between delayed primacy performance and generalized cognitive decline in cognitively intact individuals, suggesting that delayed primacy consolidation may serve as a sensitive marker of hippocampal health in these individuals.
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| 3. |
- Bruno, Davide, et al.
(författare)
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The relationship between CSF tau markers, hippocampal volume and delayed primacy performance in cognitively intact elderly individuals.
- 2015
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Ingår i: Alzheimer's & dementia : diagnosis, assessment & disease monitoring. - : Wiley. - 2352-8729. ; 1:1, s. 81-86
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Tidskriftsartikel (refereegranskat)abstract
- Primacy performance in recall has been shown to predict cognitive decline in cognitively intact elderly, and conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Delayed primacy performance, but not delayed non-primacy performance, has been shown to be associated with hippocampal volume in cognitively intact older individuals. Since presence of neurofibrillary tangles is an early sign of AD-related pathology, we set out to test whether cerebrospinal fluid (CSF) levels of tau had an effect on delayed primacy performance, while controlling for hippocampal volume and CSF Aβ 1-42 levels.
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| 4. |
- Grothe, Michel J., et al.
(författare)
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Differential diagnosis of amnestic dementia patients based on an FDG-PET signature of autopsy-confirmed LATE-NC.
- 2022
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 19:4, s. 1234-44
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Tidskriftsartikel (refereegranskat)abstract
- Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We studied whether an autopsy-derived fluorodeoxyglucose positron emission tomography (FDG-PET) signature of LATE-NC provides clinical utility for differential diagnosis of amnestic dementia patients.Ante mortem FDG-PET patterns from autopsy-confirmed LATE-NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG-PET profiles.Autopsy-confirmed LATE-NC and AD groups showed markedly distinct temporo-limbic and temporo-parietal FDG-PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE-NC-like FDG-PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory-predominant profile and a generally slower disease course.An autopsy-derived temporo-limbic FDG-PET signature identifies older amnestic patients whose clinical, genetic, and molecular biomarker features are consistent with underlying LATE-NC.
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| 5. |
- Grothe, Michel J, et al.
(författare)
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Molecular properties underlying regional vulnerability to Alzheimer's disease pathology.
- 2018
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 141:9
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid deposition and neurofibrillary degeneration in Alzheimer's disease specifically affect discrete neuronal systems, but the underlying mechanisms that render some brain regions more vulnerable to Alzheimer's disease pathology than others remain largely unknown. Here we studied molecular properties underlying these distinct regional vulnerabilities by analysing Alzheimer's disease-typical neuroimaging patterns of amyloid deposition and neurodegeneration in relation to regional gene expression profiles of the human brain. Graded patterns of brain-wide vulnerability to amyloid deposition and neurodegeneration in Alzheimer's disease were estimated by contrasting multimodal amyloid-sensitive PET and structural MRI data between patients with Alzheimer's disease dementia (n = 76) and healthy controls (n = 126) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen brain atlas of the adult human brain transcriptome. In a hypothesis-driven analysis focusing on the genes coding for the amyloid precursor (APP) and tau proteins (MAPT), regional expression levels of APP were positively correlated with the severity of regional amyloid deposition (r = 0.44, P = 0.009), but not neurodegeneration (r = 0.01, P = 0.96), whereas the opposite pattern was observed for MAPT (neurodegeneration: r = 0.46, P = 0.006; amyloid: r = 0.08, P = 0.65). Using explorative gene set enrichment analysis, amyloid-vulnerable regions were found to be characterized by relatively low expression levels of gene sets implicated in protein synthesis and mitochondrial respiration. By contrast, neurodegeneration-vulnerable regions were characterized by relatively high expression levels of gene sets broadly implicated in neural plasticity, with biological functions ranging from neurite outgrowth and synaptic contact over intracellular signalling cascades to proteoglycan metabolism. At the individual gene level this data-driven analysis further corroborated the association between neurodegeneration and MAPT expression, and additionally identified associations with known tau kinases (CDK5, MAPK1/ERK2) alongside components of their intracellular (Ras-ERK) activation pathways. Sensitivity analyses showed that these pathology-specific imaging-genetic associations were largely robust against changes in some of the methodological parameters, including variation in the brain donor sample used for estimating regional gene expression profiles, and local variations in the Alzheimer's disease-typical imaging patterns when these were derived from an independent patient cohort (BioFINDER study). These findings highlight that the regionally selective vulnerability to Alzheimer's disease pathology relates to specific molecular-functional properties of the affected neural systems, and that the implicated biochemical pathways largely differ for amyloid accumulation versus neurodegeneration. The data provide novel insights into the complex pathophysiological mechanisms of Alzheimer's disease and point to pathology-specific treatment targets that warrant further exploration in independent studies.
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| 6. |
- Kleineidam, Luca, et al.
(författare)
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Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve
- 2022
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Ingår i: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 13
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Tidskriftsartikel (refereegranskat)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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| 7. |
- Levin, Fedor, et al.
(författare)
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Longitudinal trajectories of cognitive reserve in hypometabolic subtypes of Alzheimer's disease
- 2024
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Ingår i: Neurobiology of Aging. - 0197-4580 .- 1558-1497. ; 135, s. 26-38
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have demonstrated resilience to AD-related neuropathology in a form of cognitive reserve (CR). In this study we investigated a relationship between CR and hypometabolic subtypes of AD, specifically the typical and the limbic-predominant subtypes. We analyzed data from 59 Aβ-positive cognitively normal (CN), 221 prodromal Alzheimer's disease (AD) and 174 AD dementia participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) from ADNI and ADNIGO/2 phases. For replication, we analyzed data from 5 Aβ-positive CN, 89 prodromal AD and 43 AD dementia participants from ADNI3. CR was estimated as standardized residuals in a model predicting cognition from temporoparietal grey matter volumes and covariates. Higher CR estimates predicted slower cognitive decline. Typical and limbic-predominant hypometabolic subtypes demonstrated similar baseline CR, but the results suggested a faster decline of CR in the typical subtype. These findings support the relationship between subtypes and CR, specifically longitudinal trajectories of CR. Results also underline the importance of longitudinal analyses in research on CR.
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| 8. |
- Berron, David, et al.
(författare)
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Higher CSF Tau Levels Are Related to Hippocampal Hyperactivity and Object Mnemonic Discrimination in Older Adults
- 2019
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 39:44, s. 8788-8797
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Tidskriftsartikel (refereegranskat)abstract
- Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTLs). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination, even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC), have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance, and levels of total and phosphorylated tau as well as Aβ42/40 ratio in CSF. We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus, and both increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects, but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline.SIGNIFICANCE STATEMENT Subregions in the human medial temporal lobe are critically involved in episodic memory and, at the same time, affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals, but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related fMRI in combination with measures of tau pathology in CSF, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.
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| 9. |
- Buerger, Katharina, et al.
(författare)
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CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease.
- 2006
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 129:Pt 11, s. 3035-41
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Tidskriftsartikel (refereegranskat)abstract
- Hyperphosphorylated tau protein (P-tau) in CSF is a core biomarker candidate of Alzheimer's disease. Hyperphosphorylation of tau is thought to lead to neurofibrillary changes, a neuropathological hallmark of this type of dementia. Currently, the question is unresolved whether CSF levels of P-tau reflect neurofibrillary changes within the brain of a patient with the illness. Twenty-six patients were included with intra-vitam CSF as well as post-mortem neuropathological data. In the CSF, P-tau phosphorylated at threonine 231 (P-tau231P) was analysed. Post-mortem, scores of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed in frontal, temporal, parietal and hippocampal cortical areas. In the same cortical regions, load of hyperphosphorylated tau protein (HP-tau load) was determined. Concentrations of P-tau231P were measured in frontal cortex homogenates. We found significant correlations between CSF P-tau231P concentrations and scores of NFTs and HP-tau load in all neocortical regions studied. The score of NPs was correlated with CSF P-tau231P only within the frontal cortex. There was a correlation between P-tau231P in CSF and brain homogenates. These findings indicate that CSF P-tau231P may serve as an in vivo surrogate biomarker of neurofibrillary pathology in Alzheimer's disease.
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| 10. |
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