| 1. |
- Janelidze, Shorena, et al.
(författare)
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Plasma beta-amyloid in Alzheimer's disease and vascular disease
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of A beta 42 and A beta 40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both A beta 42 and A beta 40, and negative correlations between plasma A beta 42 and neocortical amyloid deposition (measured with PET). Plasma levels of A beta 42 and A beta 40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of A beta 42 was just moderately decreased whereas A beta 40 levels were unchanged. Higher plasma (but not CSF) levels of A beta were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma A beta is overtly decreased during the dementia stage of AD indicating that prominent changes in A beta metabolism occur later in the periphery compared to the brain. Further, increased levels of A beta in plasma are associated with vascular disease.
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| 2. |
- Baumeister, Hannah, et al.
(författare)
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A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
- 2024
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
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Tidskriftsartikel (refereegranskat)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. |
- Harper, Luke, et al.
(författare)
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Prenatal Gyrification Pattern Affects Age at Onset in Frontotemporal Dementia
- 2022
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 32:18, s. 3937-3944
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Tidskriftsartikel (refereegranskat)abstract
- The paracingulate sulcus is a tertiary sulcus formed during the third trimester. In healthy individuals paracingulate sulcation is more prevalent in the left hemisphere. The anterior cingulate and paracingulate gyri are focal points of neurodegeneration in behavioral variant frontotemporal dementia (bvFTD). This study aims to determine the prevalence and impact of paracingulate sulcation in bvFTD. Structural magnetic resonance images of individuals with bvFTD (n = 105, mean age 66.9 years), Alzheimer's disease (n = 92, 73.3), and healthy controls (n = 110, 62.4) were evaluated using standard protocol for hemispheric paracingulate sulcal presence. No difference in left hemisphere paracingulate sulcal frequency was observed between groups; 0.72, 0.79, and 0.70, respectively, in the bvFTD, Alzheimer's disease, and healthy control groups, (P = 0.3). A significant impact of right (but not left) hemispheric paracingulate sulcation on age at disease onset was identified in bvFTD (mean 60.4 years where absent vs. 63.8 where present [P = 0.04, Cohen's d = 0.42]). This relationship was not observed in Alzheimer's disease. These findings demonstrate a relationship between prenatal neuronal development and the expression of a neurodegenerative disease providing a gross morphological example of brain reserve.
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| 4. |
- Ossenkoppele, Rik, et al.
(författare)
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Distinct tau PET patterns in atrophy-defined subtypes of Alzheimer's disease
- 2020
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:2, s. 335-344
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) “typical”, (2) “limbic-predominant”, (3) “hippocampal-sparing”, and (4) “mild atrophy”. We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes. Methods: The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-β–positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline. Results: Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline. Discussion: Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.
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| 5. |
- Owens-Walton, Conor, et al.
(författare)
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Increased functional connectivity of thalamic subdivisions in patients with Parkinson’s disease
- 2019
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson’s disease (PD) affects 2–3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n = 32) compared to Controls (n = 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.
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| 6. |
- Owens-Walton, Conor, et al.
(författare)
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Structural and functional neuroimaging changes associated with cognitive impairment and dementia in Parkinson's disease
- 2021
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Ingår i: Psychiatry Research - Neuroimaging. - : Elsevier BV. - 0925-4927. ; 312
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Tidskriftsartikel (refereegranskat)abstract
- This study seeks a better understanding of possible pathophysiological mechanisms associated with cognitive impairment and dementia in Parkinson's disease using structural and functional MRI. We investigated resting-state functional connectivity of important subdivisions of the caudate nucleus, putamen and thalamus, and also how the morphology of these structures are impacted in the disorder. We found cognitively unimpaired Parkinson's disease subjects (n = 33), compared to controls (n = 26), display increased functional connectivity of the dorsal caudate, anterior putamen and mediodorsal thalamic subdivisions with areas across the frontal lobe, as well as reduced functional connectivity of the dorsal caudate with posterior cortical and cerebellar regions. Compared to cognitively unimpaired subjects, those with mild cognitive impairment (n = 22) demonstrated reduced functional connectivity of the mediodorsal thalamus with the paracingulate cortex, while also demonstrating increased functional connectivity of the mediodorsal thalamus with the posterior cingulate cortex, compared to subjects with dementia (n = 17). Extensive volumetric and surface-based deflation was found in subjects with dementia compared to cognitively unimpaired Parkinson's disease participants and controls. Our research suggests that structures within basal ganglia-thalamocortical circuits are implicated in cognitive impairment and dementia in Parkinson's disease, with cognitive impairment and dementia associated with a breakdown in functional connectivity of the mediodorsal thalamus with para- and posterior cingulate regions of the brain respectively.
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| 7. |
- Spotorno, Nicola, et al.
(författare)
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Astrocytic function is associated with both amyloid-β and tau pathology in non-demented APOE 4 carriers
- 2022
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimer's disease. Given that APOE is primarily expressed in astrocytes, these cells might be an important link between the APOE ϵ4 allele and the development of Alzheimer's disease pathology. Here, we investigate this hypothesis in vivo by measuring myo-inositol, a metabolite involved in astrocytic functions, with magnetic resonance spectroscopy. Currently, there is conflicting evidence regarding the relationship between APOE ϵ4 and myo-inositol concentration. Furthermore, data supporting a relationship between APOE ϵ4, myo-inositol and Alzheimer's disease pathology (amyloid-beta and tau proteins) in the preclinical stage of Alzheimer's disease are limited. A previous study revealed differences in myo-inositol levels between APOE ϵ4 carriers and non-carriers already in preclinical Alzheimer's disease participants. However, other reports showed no impact of APOE genotype on the association between myo-inositol and the rate of amyloid-beta accumulation. In the present study, we determined the effect of APOE genotype on the association between myo-inositol and both amyloid-β and tau deposition quantified by PET in 428 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. APOE genotype impacted the associations between myo-inositol and amyloid-β pathology as revealed by an interaction effect between APOE genotype and levels of myo-inositol (P < 0.001) such that higher myo-inositol concentration was related to more amyloid-beta pathology in APOE ϵ4 carriers only. A similar interaction effect was also found when investigating the effect of APOE on the association between myo-inositol and tau pathology (P < 0.01). Focusing on the APOE ϵ4 subsample, myo-inositol partially (17%) mediated the association between amyloid-beta and tau pathology (P < 0.05). Furthermore, in a subgroup of participants with available plasma levels of glial fibrillary acidic protein, a marker of astroglial activation and astrocytosis, we found that glial fibrillary acidic protein correlated with myo-inositol only in APOE e4 carriers (APOE ϵ4 carriers: P < 0.01; APOE ϵ4 non-carriers: P > 0.8), suggesting that myo-inositol might reflect an aspect of the astrocytic involvement in Alzheimer's pathology which is specific to the impact of APOE ϵ4. Therefore, we suggest that myo-inositol is a candidate in vivo marker to study the impact of APOE ϵ4 on the interplay between astrocytes and the pathophysiology of Alzheimer's disease.
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