Publications by authors named "Joana B Pereira"

71 Publications

Deep learning from MRI-derived labels enables automatic brain tissue classification on human brain CT.

Neuroimage 2021 Sep 25;244:118606. Epub 2021 Sep 25.

Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Psychiatry and Neurochemistry, Institute of Physiology and Neuroscience, University of Gothenburg, Gothenburg, Sweden; Dementia Research Centre, Institute of Neurology, University College London, London, UK; Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address:

Automatic methods for feature extraction, volumetry, and morphometric analysis in clinical neuroscience typically operate on images obtained with magnetic resonance (MR) imaging equipment. Although CT scans are less expensive to acquire and more widely available than MR scans, their application is currently limited to the visual assessment of brain integrity and the exclusion of co-pathologies. CT has rarely been used for tissue classification because the contrast between grey matter and white matter was considered insufficient. In this study, we propose an automatic method for segmenting grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), and intracranial volume (ICV) from head CT images. A U-Net deep learning model was trained and validated on CT images with MRI-derived segmentation labels. We used data from 744 participants of the Gothenburg H70 Birth Cohort Studies for whom CT and T1-weighted MR images had been acquired on the same day. Our proposed model predicted brain tissue classes accurately from unseen CT images (Dice coefficients of 0.79, 0.82, 0.75, 0.93 and 0.98 for GM, WM, CSF, brain volume and ICV, respectively). To contextualize these results, we generated benchmarks based on established MR-based methods and intentional image degradation. Our findings demonstrate that CT-derived segmentations can be used to delineate and quantify brain tissues, opening new possibilities for the use of CT in clinical practice and research.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118606DOI Listing
September 2021

Atrial Fibrillation, Stroke, and Silent Cerebrovascular Disease: A Population-based MRI Study.

Neurology 2021 Oct 14;97(16):e1608-e1619. Epub 2021 Sep 14.

From the Institute of Neuroscience and Physiology (L.R., S.Sacuiu, H.W., J.N., X.G., S.K., A.Z., I.S.), Sahlgrenska Academy, Centre for Ageing and Health at the University of Gothenburg; Department of Psychiatry Cognition and Old Age Psychiatry (L.R., S.S., J.N., S.K., I.S.), Sahlgrenska University Hospital, Region Västra Götaland, Mölndal; Department of Mood Disorders (X.G.), Sahlgrenska University Hospital, Region Västra Götaland, Göteborg; Division of Clinical Geriatrics (S.Shams, J.B.P., L.-O.W., E.W.), Centre for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden; Department of Radiology (S.S.), Stanford, CA; and Clinical Memory Research Unit (J.B.P.), Department of Clinical Sciences, Malmö, Lund University, Sweden.

Background And Objectives: Atrial fibrillation (AF) has been associated with cognitive decline and dementia. However, the mechanisms behind these associations are not clear. Examination of cerebrovascular pathology on MRI may shed light on how AF affects the brain. This study aimed to determine whether AF is associated with a broad range of cerebrovascular diseases beyond the well-known association with symptomatic stroke, including silent infarcts and markers of small vessel disease, i.e., cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), and lacunes, in a population-based sample of 70-year-olds.

Methods: Data were obtained from the Gothenburg H70 Birth Cohort Studies, in which individuals are invited based on birthdate. This study has a cross-sectional design and includes individuals born in 1944 who underwent structural brain MRI in 2014 to 2017. AF diagnoses were based on self-report, ECG, and register data. Symptomatic stroke was based on self-report, proxy interviews, and register data. Brain infarcts and CMBs were assessed by a radiologist. WMH volumes were measured on fluid-attenuated inversion recovery images with the Lesion Segmentation Tool. Multivariable logistic regression was used to study the association between AF and infarcts/CMBs, and multivariable linear regression was used to study the association between AF and WMHs.

Results: A total of 776 individuals were included, and 65 (8.4%) had AF. AF was associated with symptomatic stroke (odds ratio [OR] 4.5, 95% confidence interval [CI] 2.1-9.5) and MRI findings of large infarcts (OR 5.0, 95% CI 1.5-15.9), lacunes (OR 2.7, 95% CI 1.2-5.6), and silent brain infarcts (OR 3.5; 95% CI 1.6-7.4). Among those with symptomatic stroke, individuals with AF had larger WMH volumes (0.0137 mL/total intracranial volume [TIV], 95% CI 0.0074-0.0252) compared to those without AF (0.0043 mL/TIV, 95% CI 0.0029-0.0064). There was no association between AF and WMH volumes among those without symptomatic stroke. In addition, AF was associated to CMBs in the frontal lobe.

Discussion: AF was associated with a broad range of cerebrovascular pathologies. Further research is needed to establish whether cerebrovascular MRI markers can be added to current treatment guidelines to further personalize anticoagulant treatment in patients with AF and to further characterize the pathogenetic processes underlying the associations between AF and cerebrovascular diseases, as well as dementia.
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http://dx.doi.org/10.1212/WNL.0000000000012675DOI Listing
October 2021

Effects of a Highly Challenging Balance Training Program on Motor Function and Brain Structure in Parkinson's Disease.

J Parkinsons Dis 2021 ;11(4):2057-2071

Division of Physiotherapy, Department of Neurobiology, Care sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Background: Parkinson's disease (PD) is characterized by motor deficits and brain alterations having a detrimental impact on balance, gait, and cognition. Intensive physical exercise can induce changes in the neural system, potentially counteracting neurodegeneration in PD and improving clinical symptoms.

Objective: This randomized controlled trial investigated effects of a highly challenging, cognitively demanding, balance and gait training (HiBalance) program in participants with PD on brain structure.

Methods: 95 participants were assigned to either the HiBalance or an active control speech training program. The group-based interventions were performed in 1-hour sessions, twice per week over a 10-week period. Participants underwent balance, gait, cognitive function, and structural magnetic resonance imaging assessments before and after the interventions. Voxel-based morphometry was analyzed in 34 HiBalance and 31 active controls. Additionally, structural covariance networks were assessed.

Results: There was no significant time by group interaction between the HiBalance and control training in balance, gait, or brain volume. Within-HiBalance-group analyses showed higher left putamen volumes post-training. In repeated measures correlation a positive linear, non-significant relationship between gait speed and putamen volume was revealed. In the HiBalance group we found community structure changes and stronger thalamic-cerebellar connectivity in structural covariance networks. Neither brain volume changes nor topology changes were found for the active controls after the training.

Conclusion: Thus, subtle structural brain changes occur after balance and gait training. Future studies need to determine whether training modifications or other assessment methods lead to stronger effects.
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http://dx.doi.org/10.3233/JPD-212801DOI Listing
January 2021

The Cognitive Connectome in Healthy Aging.

Front Aging Neurosci 2021 18;13:694254. Epub 2021 Aug 18.

Department of Clinical Psychology, Psychobiology and Methodology, Faculty of Psychology, University of La Laguna, La Laguna, Spain.

: Cognitive aging has been extensively investigated using both univariate and multivariate analyses. Sophisticated multivariate approaches such as graph theory could potentially capture unknown complex associations between multiple cognitive variables. The aim of this study was to assess whether cognition is organized into a structure that could be called the "cognitive connectome," and whether such connectome differs between age groups. : A total of 334 cognitively unimpaired individuals were stratified into early-middle-age (37-50 years, = 110), late-middle-age (51-64 years, = 106), and elderly (65-78 years, = 118) groups. We built cognitive networks from 47 cognitive variables for each age group using graph theory and compared the groups using different global and nodal graph measures. : We identified a cognitive connectome characterized by five modules: verbal memory, visual memory-visuospatial abilities, procedural memory, executive-premotor functions, and processing speed. The elderly group showed reduced transitivity and average strength as well as increased global efficiency compared with the early-middle-age group. The late-middle-age group showed reduced global and local efficiency and modularity compared with the early-middle-age group. Nodal analyses showed the important role of executive functions and processing speed in explaining the differences between age groups. : We identified a cognitive connectome that is rather stable during aging in cognitively healthy individuals, with the observed differences highlighting the important role of executive functions and processing speed. We translated the connectome concept from the neuroimaging field to cognitive data, demonstrating its potential to advance our understanding of the complexity of cognitive aging.
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http://dx.doi.org/10.3389/fnagi.2021.694254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416612PMC
August 2021

Tau-related grey matter network breakdown across the Alzheimer's disease continuum.

Alzheimers Res Ther 2021 08 13;13(1):138. Epub 2021 Aug 13.

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.

Background: Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-β (Aβ) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum.

Methods: We included 533 individuals (178 Aβ-negative cognitively unimpaired (CU) subjects, 105 Aβ-positive CU subjects, 122 Aβ-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions.

Results: Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aβ-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology.

Conclusions: Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.
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http://dx.doi.org/10.1186/s13195-021-00876-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364121PMC
August 2021

Directed Brain Connectivity Identifies Widespread Functional Network Abnormalities in Parkinson's Disease.

Cereb Cortex 2021 Jul 30. Epub 2021 Jul 30.

Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm 14183, Sweden.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by topological abnormalities in large-scale functional brain networks, which are commonly analyzed using undirected correlations in the activation signals between brain regions. This approach assumes simultaneous activation of brain regions, despite previous evidence showing that brain activation entails causality, with signals being typically generated in one region and then propagated to other ones. To address this limitation, here, we developed a new method to assess whole-brain directed functional connectivity in participants with PD and healthy controls using antisymmetric delayed correlations, which capture better this underlying causality. Our results show that whole-brain directed connectivity, computed on functional magnetic resonance imaging data, identifies widespread differences in the functional networks of PD participants compared with controls, in contrast to undirected methods. These differences are characterized by increased global efficiency, clustering, and transitivity combined with lower modularity. Moreover, directed connectivity patterns in the precuneus, thalamus, and cerebellum were associated with motor, executive, and memory deficits in PD participants. Altogether, these findings suggest that directional brain connectivity is more sensitive to functional network differences occurring in PD compared with standard methods, opening new opportunities for brain connectivity analysis and development of new markers to track PD progression.
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http://dx.doi.org/10.1093/cercor/bhab237DOI Listing
July 2021

Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease.

Brain 2021 Jul 14. Epub 2021 Jul 14.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden.

Although recent clinical trials targeting amyloid-β (Aβ) in Alzheimer's disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with Aβ metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in AD. However, to this date, no studies have assessed whether astrocytosis is independently related to either Aβ or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 Aβ-negative cognitively unimpaired individuals, 71 Aβ-positive cognitively unimpaired individuals, 78 Aβ-positive cognitively impaired individuals, 63 Aβ-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal Aβ (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all Aβ-positive groups compared with subjects without Aβ pathology (p < 0.01). In addition, there were significant associations between plasma GFAP with higher Aβ-PET signal in all Aβ-positive groups, but also in cognitively normal individuals with normal Aβ values (p < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict Aβ-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for Aβ-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p < 0.05) and correlated with Aβ-PET only in Aβ-positive cognitively impaired individuals (p = 0.005). Finally, plasma GFAP was associated with both longitudinal Aβ-PET and cognitive decline, and mediated the effect of Aβ-PET on tau-PET burden, suggesting that astrocytosis secondary to Aβ aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain Aβ pathology but not tau aggregation, even in cognitively normal individuals with a normal Aβ status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to Aβ pathology.
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http://dx.doi.org/10.1093/brain/awab223DOI Listing
July 2021

Dendritic spines are lost in clusters in Alzheimer's disease.

Sci Rep 2021 06 11;11(1):12350. Epub 2021 Jun 11.

Laboratorio Cajal de Circuitos Corticales (CTB), Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Campus Montegancedo S/N, Pozuelo de Alarcon, 28223, Madrid, Spain.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. The pathological accumulation of tau in neurons is one of the hallmarks of AD and has been connected to the loss of dendritic spines of pyramidal cells, which are the major targets of cortical excitatory synapses and key elements in memory storage. However, the detailed mechanisms underlying the loss of dendritic spines in individuals with AD are still unclear. Here, we used graph-theory approaches to compare the distribution of dendritic spines from neurons with and without tau pathology of AD individuals. We found that the presence of tau pathology determines the loss of dendritic spines in clusters, ruling out alternative models where spine loss occurs at random locations. Since memory storage has been associated with synaptic clusters, the present results provide a new insight into the mechanisms by which tau drives synaptic damage in AD, paving the way to memory deficits through alterations of spine organization.
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http://dx.doi.org/10.1038/s41598-021-91726-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196005PMC
June 2021

Sex differences in off-target binding using tau positron emission tomography.

Neuroimage Clin 2021 29;31:102708. Epub 2021 May 29.

Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden.

Purpose: Off-target binding in the skull and meninges is observed in some subjects undergoing tau positron emission tomography (PET) and could potentially differ between men and women. In this study we elucidate sex differences in tau off-target binding using three different tau PET tracers.

Methods: 541 cognitively unimpaired amyloid-β negative participants underwent tau PET using [F]flortaucipir (n = 165), [F]RO948 (n = 189) and [F]MK6240 (n = 187). Baseline SUVR-values were compared between females and males at the voxel level and using a region-of-interest (ROI) encompassing the skull/meninges. In addition, we assessed the cross-sectional relationship between baseline skull/meninges SUVR and age and assessed change in skull/meningeal SUVR values over time in a subsample with longitudinal data (n = 63).

Results: Voxel-wise analysis showed higher meningeal off-target binding in women compared to men across all three tracers. The SUVRs in the skull/meningeal ROI were highest using [F]RO948, followed by [F]MK6240 and [F]flortaucipir (p < 0.001). For all tracers, females showed higher skull/meningeal ROI retention (mean SUVR ± SD [F]flortaucipir: 0.82 ± 0.14; [F]RO948: 1.26 ± 0.30; [F]MK6240: 1.09 ± 0.19) compared to men ([F]flortaucipir: 0.70 ± 0.11; [F]RO948: 1.10 ± 0.24; [F]MK6240: 0.97 ± 0.17) (p < 0.001). For [F]flortaucipir and [F]RO948, off-target binding in the skull/meninges decreased with age.

Conclusion: There is an effect of sex on off-target retention in the meninges/skull across [F]flortaucipir, [F]RO948, and [F]MK6240 tau PET tracers.
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http://dx.doi.org/10.1016/j.nicl.2021.102708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182304PMC
September 2021

Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects.

Brain 2021 Jun 2. Epub 2021 Jun 2.

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, SE-20502 Malmö, Sweden.

It is currently unclear whether plasma biomarkers can be used as independent prognostic tools to predict changes associated with early Alzheimer's disease (AD). In this study we sought to address this question by assessing whether plasma biomarkers can predict changes in amyloid load, tau accumulation, brain atrophy and cognition in non-demented individuals. To achieve this, plasma amyloid-β 42/40 (Aβ42/40), phosphorylated-tau181 (P-tau181), phosphorylated-tau217 (P-tau217) and neurofilament light (NfL) were determined in 159 non-demented individuals, 123 patients with AD dementia and 35 patients with a non-AD dementia from the Swedish BioFINDER-2 study, who underwent longitudinal amyloid (18 F-flutemetamol) and tau (18 F-RO948) positron emission tomography (PET), structural magnetic resonance imaging (T1-weighted) and cognitive testing. Our univariate linear mixed effect models showed there were several significant associations between the plasma biomarkers with imaging and cognitive measures. However, when all biomarkers were included in the same multivariate linear mixed effect models, we found that increased longitudinal amyloid-PET signals were independently predicted by low baseline plasma Aβ42/40 (p = 0.012), whereas increased tau-PET signals, brain atrophy and worse cognition were independently predicted by high plasma P-tau217 (p < 0.004). These biomarkers performed equally well or better than the corresponding biomarkers measured in the cerebrospinal fluid. In addition, they showed a similar performance to binary plasma biomarker values defined using the Youden index, which can be more easily implemented in the clinic. In addition, plasma Aβ42/40 and P-tau217 did not predict longitudinal changes in patients with a non-AD neurodegenerative disorder. In conclusion, our findings indicate that plasma Aβ42/40 and P-tau217 could be useful in clinical practice, research and drug development as prognostic markers of future AD pathology.
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http://dx.doi.org/10.1093/brain/awab163DOI Listing
June 2021

Cortical Networks Underpinning Compensation of Verbal Fluency in Normal Aging.

Cereb Cortex 2021 Jul;31(8):3832-3845

Department of Clinical Psychology, Psychobiology and Methodology, Faculty of Health Science, Section of Psychology and Speech Therapy, University of La Laguna, La Laguna, Tenerife 38 200, Spain.

Elucidating compensatory mechanisms underpinning phonemic fluency (PF) may help to minimize its decline due to normal aging or neurodegenerative diseases. We investigated cortical brain networks potentially underpinning compensation of age-related differences in PF. Using graph theory, we constructed networks from measures of thickness for PF, semantic, and executive-visuospatial cortical networks. A total of 267 cognitively healthy individuals were divided into younger age (YA, 38-58 years) and older age (OA, 59-79 years) groups with low performance (LP) and high performance (HP) in PF: YA-LP, YA-HP, OA-LP, OA-HP. We found that the same pattern of reduced efficiency and increased transitivity was associated with both HP (compensation) and OA (aberrant network organization) in the PF and semantic cortical networks. When compared with the OA-LP group, the higher PF performance in the OA-HP group was associated with more segregated PF and semantic cortical networks, greater participation of frontal nodes, and stronger correlations within the PF cortical network. We conclude that more segregated cortical networks with strong involvement of frontal nodes seemed to allow older adults to maintain their high PF performance. Nodal analyses and measures of strength were helpful to disentangle compensation from the aberrant network organization associated with OA.
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http://dx.doi.org/10.1093/cercor/bhab052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258442PMC
July 2021

Early stages of tau pathology and its associations with functional connectivity, atrophy and memory.

Brain 2021 Mar 16. Epub 2021 Mar 16.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 223 62 Lund, Sweden.

In Alzheimer's disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 β-amyloid negative cognitively unimpaired, 81 β-amyloid positive cognitively unimpaired and 87 β-amyloid positive individuals with mild cognitive impairment, who each underwent [18]F-RO948 tau and [18]F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease-stage specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.
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http://dx.doi.org/10.1093/brain/awab114DOI Listing
March 2021

Effects of amyloid pathology and the APOE ε4 allele on the association between cerebrospinal fluid Aβ38 and Aβ40 and brain morphology in cognitively normal 70-years-olds.

Neurobiol Aging 2021 05 12;101:1-12. Epub 2021 Jan 12.

Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry Cognition and Old Age Psychiatry Clinic, Mölndal, Sweden; Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Mölndal, Sweden.

The association between cerebrospinal fluid (CSF) amyloid beta (Aβ) Aβ38 or Aβ40 and brain grey- and white matter integrity is poorly understood. We studied this in 213 cognitively normal 70-year-olds, and in subgroups defined by presence/absence of the APOE ε4 allele and Aβ pathology: Aβ-/APOE-, Aβ+/APOE-, Aβ-/APOE+ and Aβ+/APOE+. CSF Aβ was quantified using ELISA and genotyping for APOE was performed. Low CSF Aβ42 defined Aβ plaque pathology. Brain volumes were assessed using Freesurfer-5.3, and white matter integrity using tract-based statistics in FSL. Aβ38 and Aβ40 were positively correlated with cortical thickness, some subcortical volumes and white matter integrity in the total sample, and in 3 of the subgroups: Aβ-/APOE-, Aβ+/APOE- and Aβ-/APOE+. In Aβ+/APOE+ subjects, higher Aβ38 and Aβ40 were linked to reduced cortical thickness and subcortical volumes. We hypothesize that production of all Aβ species decrease in brain regions with atrophy. In Aβ+/APOE+, Aβ-dysregulation may be linked to cortical atrophy in which high Aβ levels is causing pathological changes in the gray matter of the brain.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.033DOI Listing
May 2021

Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer's disease.

Brain 2021 02;144(1):310-324

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.

It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer's disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer's disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.
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http://dx.doi.org/10.1093/brain/awaa395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210638PMC
February 2021

Detecting early changes in Alzheimer's disease with graph theory.

Authors:
Joana B Pereira

Brain Commun 2020 18;2(2):fcaa129. Epub 2020 Aug 18.

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm 141 83, Sweden.

This scientific commentary refers to 'Single-subject grey matter network trajectories over the disease course of autosomal dominant Alzheimer disease', by Vermunt et al. (https://doi.org/10.1093/braincomms/fcaa102).
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http://dx.doi.org/10.1093/braincomms/fcaa129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667723PMC
August 2020

Increased Cerebrospinal Fluid Concentration of ZnT3 Is Associated with Cognitive Impairment in Alzheimer's Disease.

J Alzheimers Dis 2020 ;77(3):1143-1155

Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.

Background: Cognitive deficits arising in the course of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease with dementia (PDD) are directly linked to synaptic loss. Postmortem studies suggest that zinc transporter protein 3 (ZnT3), AMPA glutamate receptor 3 (GluA3), and Dynamin1 are associated with cognitive decline in AD and Lewy body dementia patients.

Objective: We aimed to evaluate the diagnostic value of ZnT3, GluA3, and Dynamin 1 in the cerebrospinal fluid (CSF) of patients with dementia due to AD, DLB, and PDD compared to cognitively normal subjective cognitive decline (SCD) patients in a retrospective study. In addition, we assessed the relationship between synaptic markers and age, sex, cognitive impairment, and depressive symptoms as well as CSF amyloid, phosphorylated tau (p-tau), and total tau (T-tau).

Methods: Commercially available ELISA immunoassay was used to measure the levels of proteins in a total of 97 CSF samples from AD (N = 24), PDD (N = 18), DLB (N = 27), and SCD (N = 28) patients. Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE).

Results: We found a significant increase in the concentrations of ZnT3, GluA3, and Dynamin1 in AD (p = 0.002) and of ZnT3 and Dynamin 1 in DLB (p = 0.001, p = 0.002) when compared to SCD patients. Changes in ZnT3 concentrations correlated with MMSE scores in AD (p = 0.011), and with depressive symptoms in SCD (p = 0.041).

Conclusion: We found alteration of CSF levels of synaptic proteins in AD, PDD, and DLB. Our results reveal distinct changes in CSF concentrations of ZnT3 that could reflect cognitive impairment in AD with implications for future prognostic and diagnostic marker development.
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http://dx.doi.org/10.3233/JAD-200498DOI Listing
September 2021

Fully bayesian longitudinal unsupervised learning for the assessment and visualization of AD heterogeneity and progression.

Aging (Albany NY) 2020 07 9;12(13):12622-12647. Epub 2020 Jul 9.

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Tau pathology and brain atrophy are the closest correlate of cognitive decline in Alzheimer's disease (AD). Understanding heterogeneity and longitudinal progression of atrophy during the disease course will play a key role in understanding AD pathogenesis. We propose a framework for longitudinal clustering that simultaneously: 1) incorporates whole brain data, 2) leverages unequal visits per individual, 3) compares clusters with a control group, 4) allows for study confounding effects, 5) provides cluster visualization, 6) measures clustering uncertainty. We used amyloid-β positive AD and negative healthy subjects, three longitudinal structural magnetic resonance imaging scans (cortical thickness and subcortical volume) over two years. We found three distinct longitudinal AD brain atrophy patterns: one typical diffuse pattern (n=34, 47.2%), and two atypical patterns: minimal atrophy (n=23 31.9%) and hippocampal sparing (n=9, 12.5%). We also identified outliers (n=3, 4.2%) and observations with uncertain classification (n=3, 4.2%). The clusters differed not only in regional distributions of atrophy at baseline, but also longitudinal atrophy progression, age at AD onset, and cognitive decline. A framework for the longitudinal assessment of variability in cohorts with several neuroimaging measures was successfully developed. We believe this framework may aid in disentangling distinct subtypes of AD from disease staging.
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http://dx.doi.org/10.18632/aging.103623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377879PMC
July 2020

Medial temporal atrophy in preclinical dementia: Visual and automated assessment during six year follow-up.

Neuroimage Clin 2020 10;27:102310. Epub 2020 Jun 10.

Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden; Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Medial temporal lobe (MTL) atrophy is an important morphological marker of many dementias and is closely related to cognitive decline. In this study we aimed to characterize longitudinal progression of MTL atrophy in 93 individuals with subjective cognitive decline and mild cognitive impairment followed up over six years, and to assess if clinical rating scales are able to detect these changes. All MRI images were visually rated according to Scheltens' scale of medial temporal atrophy (MTA) by two neuroradiologists and AVRA, a software for automated MTA ratings. The images were also segmented using FreeSurfer's longitudinal pipeline in order to compare the MTA ratings to volumes of the hippocampi and inferior lateral ventricles. We found that MTL atrophy rates increased with CSF biomarker abnormality, used to define preclinical stages of Alzheimer's Disease. Both AVRA's and the radiologists' MTA ratings showed similar longitudinal trends as the subcortical volumes, suggesting that visual rating scales provide a valid alternative to automatic segmentations. Our results further showed that it took more than 8 years on average for individuals with mild cognitive impairment, and an Alzheimer's disease biomarker profile, to increase the MTA score by one. This suggests that discrete MTA ratings are too coarse for tracking individual MTL atrophy in short time spans. While the MTA scores from each radiologist showed strong correlations to subcortical volumes, the inter-rater agreement was low. We conclude that the main limitation of quantifying MTL atrophy with visual ratings in clinics is the subjectiveness of the assessment.
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http://dx.doi.org/10.1016/j.nicl.2020.102310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317671PMC
June 2021

Relevance of biomarkers across different neurodegenerative diseases.

Alzheimers Res Ther 2020 05 13;12(1):56. Epub 2020 May 13.

Dementia Research Centre, University College London Institute of Neurology, London, UK.

Background: The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field.

Purpose Of Review: Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.
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http://dx.doi.org/10.1186/s13195-020-00601-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222479PMC
May 2020

Imaging biomarkers in neurodegeneration: current and future practices.

Alzheimers Res Ther 2020 04 27;12(1):49. Epub 2020 Apr 27.

Wallenberg Centre for Molecular and Translational Medicine and the Department of Psychiatry and Neurochemistry, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course "Biomarkers in neurodegenerative diseases". In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.
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http://dx.doi.org/10.1186/s13195-020-00612-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187531PMC
April 2020

Longitudinal degeneration of the basal forebrain predicts subsequent dementia in Parkinson's disease.

Neurobiol Dis 2020 06 5;139:104831. Epub 2020 Mar 5.

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmo, Sweden; Memory Clinic, Skåne University Hospital, Malmo, Sweden. Electronic address:

Objectives: Cholinergic dysfunction plays a prominent role in cognitive impairment in Parkinson's disease (PD). The aim of this study was to assess the relationship of baseline and longitudinal basal forebrain atrophy with cognitive decline and dementia in PD.

Methods: We included 106 non-demented PD patients, 19 PD dementia (PDD) patients and 42 controls with longitudinal structural MRI and cognitive testing. After 4.2 ± 1.8 years, 20 non-demented PD patients were diagnosed with dementia (PD-dementia converters), whereas the rest of PD patients remained non-demented (stable-PD). We compared MRI volumes of the medial septum/diagonal band (Ch1/Ch2) and nucleus basalis of Meynert (Ch4) between groups. Cox regression analyses were applied to test whether Ch1/Ch2 or Ch4 atrophy could predict future dementia and linear mixed models assessed their association with cognitive decline.

Results: Compared to controls, we found reduced Ch4 baseline volumes in PD-dementia converters (p = .003) and those who already had PDD (p < .001) but not in stable-PD. Over time, there was a greater loss in Ch1/Ch2 volumes in PD-dementia converters and PDD compared to the other groups (p = .004). Baseline and longitudinal Ch4 volumes were associated with cognition (p < .002) and longitudinal Ch4 atrophy predicted future dementia (p = .009).

Conclusions: Atrophy of Ch4 precedes and predicts future dementia in PD and is followed by changes in Ch1/Ch2, reflecting a posterior-anterior pattern of basal forebrain atrophy. This pattern could be used to track the spread of cholinergic degeneration and identify patients at risk of developing dementia.
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http://dx.doi.org/10.1016/j.nbd.2020.104831DOI Listing
June 2020

Delayed correlations improve the reconstruction of the brain connectome.

PLoS One 2020 19;15(2):e0228334. Epub 2020 Feb 19.

Department of Physics, University of Gothenburg, Gothenburg, Sweden.

The brain works as a large-scale complex network, known as the connectome. The strength of the connections between two brain regions in the connectome is commonly estimated by calculating the correlations between their patterns of activation. This approach relies on the assumption that the activation of connected regions occurs together and at the same time. However, there are delays between the activation of connected regions due to excitatory and inhibitory connections. Here, we propose a method to harvest this additional information and reconstruct the structural brain connectome using delayed correlations. This delayed-correlation method correctly identifies 70% to 80% of connections of simulated brain networks, compared to only 5% to 25% of connections detected by the standard methods; this result is robust against changes in the network parameters (small-worldness, excitatory vs. inhibitory connection ratio, weight distribution) and network activation dynamics. The delayed-correlation method predicts more accurately both the global network properties (characteristic path length, global efficiency, clustering coefficient, transitivity) and the nodal network properties (nodal degree, nodal clustering, nodal global efficiency), particularly at lower network densities. We obtain similar results in networks derived from animal and human data. These results suggest that the use of delayed correlations improves the reconstruction of the structural brain connectome and open new possibilities for the analysis of the brain connectome, as well as for other types of networks.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228334PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029855PMC
April 2020

Cerebrospinal fluid progranulin is associated with increased cortical thickness in early stages of Alzheimer's disease.

Neurobiol Aging 2020 04 20;88:61-70. Epub 2019 Dec 20.

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Huddinge, Sweden.

Progranulin plays an important role in neuroinflammation in Alzheimer's disease (AD) pathophysiology, being upregulated by activated microglia. This study assessed whether cerebrospinal fluid levels of progranulin correlated with structural neuroimaging measures and cognition in 122 cognitively normal individuals, 81 mild cognitive impairment, and 70 AD patients from the Alzheimer's Disease Neuroimaging Initiative. Cognitively normal subjects were classified into 3 groups using the AT(N) system, whereas all mild cognitive impairment and AD patients were A+/TN+. Correlations between progranulin with neuroanatomical measures and cognitive decline were performed within each group. Progranulin was associated with cortical thickening in parietal, occipital, and frontal regions in cognitively normal individuals with amyloid pathology. These subjects also showed cortical thickening compared with A-/TN- subjects, an effect that was partially mediated by progranulin. In addition, higher progranulin correlated with longitudinal cognitive decline. The association between progranulin and cortical thickening, together with regional "brain swelling" in A+/TN- subjects, suggests progranulin contributes to the neuroinflammatory structural changes in preclinical AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.12.012DOI Listing
April 2020

Spatial patterns of tau deposition are associated with amyloid, ApoE, sex, and cognitive decline in older adults.

Eur J Nucl Med Mol Imaging 2020 08 8;47(9):2155-2164. Epub 2020 Jan 8.

Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.

Purpose: The abnormal deposition of tau begins before the onset of clinical symptoms and seems to target specific brain networks. The aim of this study is to identify the spatial patterns of tau deposition in cognitively normal older adults and assess whether they are related to amyloid-β (Aβ), APOE, sex, and longitudinal cognitive decline.

Methods: We included 114 older adults with cross-sectional flortaucipir (FTP) and Pittsburgh Compound-B PET in addition to longitudinal cognitive testing. A voxel-wise independent component analysis was applied to FTP images to identify the spatial patterns of tau deposition. We then assessed whether tau within these patterns differed by Aβ status, APOE genotype, and sex. Linear mixed effects models were built to test whether tau in each component predicted cognitive decline. Finally, we ordered the spatial components based on the frequency of high tau deposition to model tau spread.

Results: We found 10 biologically plausible tau patterns in the whole sample. There was greater tau in medial temporal, occipital, and orbitofrontal components in Aβ-positive compared with Aβ-negative individuals; in the parahippocampal component in ε3ε3 compared with ε2ε3 carriers; and in temporo-parietal and anterior frontal components in women compared with men. Higher tau in temporal and frontal components predicted longitudinal cognitive decline in memory and executive functions, respectively. Tau deposition was most frequently observed in medial temporal and ventral cortical areas, followed by lateral and primary areas.

Conclusions: These findings suggest that the spatial patterns of tau in asymptomatic individuals are clinically meaningful and are associated with Aβ, APOE ε2ε3, sex and cognitive decline. These patterns could be used to predict the regional spread of tau and perform in vivo tau staging in older adults.
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http://dx.doi.org/10.1007/s00259-019-04669-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338820PMC
August 2020

Amyloid and tau accumulate across distinct spatial networks and are differentially associated with brain connectivity.

Elife 2019 12 9;8. Epub 2019 Dec 9.

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.

The abnormal accumulation of amyloid-β and tau targets specific spatial networks in Alzheimer's disease. However, the relationship between these networks across different disease stages and their association with brain connectivity has not been explored. In this study, we applied a joint independent component analysis to F- Flutemetamol (amyloid-β) and F-Flortaucipir (tau) PET images to identify amyloid-β and tau networks across different stages of Alzheimer's disease. We then assessed whether these patterns were associated with resting-state functional networks and white matter tracts. Our analyses revealed nine patterns that were linked across tau and amyloid-β data. The amyloid-β and tau patterns showed a fair to moderate overlap with distinct functional networks but only tau was associated with white matter integrity loss and multiple cognitive functions. These findings show that amyloid-β and tau have different spatial affinities, which can be used to understand how they accumulate in the brain and potentially damage the brain's connections.
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http://dx.doi.org/10.7554/eLife.50830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938400PMC
December 2019

A quick test of cognitive speed can predict development of dementia in Parkinson's disease.

Sci Rep 2019 10 28;9(1):15417. Epub 2019 Oct 28.

Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.

Parkinson's disease (PD) patients frequently develop cognitive impairment. There is a need for brief clinical assessments identifying PD patients at high risk of progressing to dementia. In this study, we look into predicting dementia in PD and underlying structural and functional correlates to cognitive decline in PD. We included 175 patients with PD, 30 with PD dementia, 51 neurologically healthy controls and 121 patients with Alzheimer's disease (AD) from Skane University Hospital, BIOFINDER cohorts. All underwent cognitive tests, including MMSE, 10-word list delayed recall (ADAS-cog), A Quick Test of cognitive speed (AQT), Letter S fluency, Clock Drawing Test (CDT) and pentagon copying. In non-demented patients with PD, abnormal AQT and CDT results predicted an increased risk of subsequent development of dementia (hazard ratio 2.2 for both). When comparing the cognitive profile between PD and AD, decreased performance on AQT, which measures attention and processing speed, was more typical in PD. Lastly, we investigated the underlying structural and functional correlates for the PD-specific test AQT with magnetic resonance imaging. In PD patients, decreased performance on AQT was associated with i) cortical thinning in temporoparietal regions, ii) changes in diffusion MRI, especially in the cingulum tract, and iii) decreased functional connectivity in posterior brain networks.
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http://dx.doi.org/10.1038/s41598-019-51505-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817840PMC
October 2019

Subtypes of Alzheimer's Disease Display Distinct Network Abnormalities Extending Beyond Their Pattern of Brain Atrophy.

Front Neurol 2019 28;10:524. Epub 2019 May 28.

Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden.

Different subtypes of Alzheimer's disease (AD) with characteristic distributions of neurofibrillary tangles and corresponding brain atrophy patterns have been identified using structural magnetic resonance imaging (MRI). However, the underlying biological mechanisms that determine this differential expression of neurofibrillary tangles are still unknown. Here, we applied graph theoretical analysis to structural MRI data to test the hypothesis that differential network disruption is at the basis of the emergence of these AD subtypes. We studied a total of 175 AD patients and 81 controls. Subtyping was done using the Scheltens' scale for medial temporal lobe atrophy, the Koedam's scale for posterior atrophy, and the Pasquier's global cortical atrophy scale for frontal atrophy. A total of 89 AD patients showed a brain atrophy pattern consistent with typical AD; 30 patients showed a limbic-predominant pattern; 29 patients showed a hippocampal-sparing pattern; and 27 showed minimal atrophy. We built brain structural networks from 68 cortical regions and 14 subcortical gray matter structures for each AD subtype and for the controls, and we compared between-group measures of integration, segregation, and modular organization. At the global level, modularity was increased and differential modular reorganization was detected in the four subtypes. We also found a decrease of transitivity in the typical and hippocampal-sparing subtypes, as well as an increase of average local efficiency in the minimal atrophy and hippocampal-sparing subtypes. We conclude that the AD subtypes have a distinct signature of network disruption associated with their atrophy patterns and further extending to other brain regions, presumably reflecting the differential spread of neurofibrillary tangles. We discuss the hypothetical emergence of these subtypes and possible clinical implications.
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http://dx.doi.org/10.3389/fneur.2019.00524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547836PMC
May 2019

Cortical structure abnormalities in females with conduct disorder prior to age 15.

Psychiatry Res Neuroimaging 2019 07 6;289:37-44. Epub 2018 Dec 6.

Department of Clinical Neuroscience, Karolinska Institute, Psychiatry Building R5:00, Karolinska, University Hospital, Stockholm 171 76, Sweden; Département de Psychiatrie, Université de Montréal, Montreal, QC, Canada.

Among females, conduct disorder (CD) before age 15 is associated with multiple adverse outcomes in adulthood. The few existing structural neuroimaging studies of females with CD report abnormalities of gray matter volumes. The present study compared cortical thickness and surface area of young women with childhood/adolescent CD and healthy women to determine whether cortical abnormalities were present in adulthood and whether they were related to prior CD. Structural brain images from 31 women with CD and 25 healthy women were analyzed using FreeSurfer. Group differences between cortical thickness and surface area were assessed using cluster-wise corrections with Monte Carlo simulations. Women with prior CD, relative to healthy women, showed: (1) reduced cortical thickness in left fusiform gyrus extending up to entorhinal cortex and lingual gyrus; (2) reduced surface area in right superior parietal cortex; (3) increased surface area in left superior temporal gyrus, and right precentral gyrus. These differences remained significant after adjusting for past comorbid disorders, current symptoms of anxiety and depression, current substance use as well as maltreatment. The study suggests that among females, CD prior to age 15 is associated with cortical structure abnormalities in brain regions involved in emotion processing and social interaction.
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http://dx.doi.org/10.1016/j.pscychresns.2018.12.004DOI Listing
July 2019

Cortical thinning in patients with REM sleep behavior disorder is associated with clinical progression.

NPJ Parkinsons Dis 2019 3;5. Epub 2019 May 3.

1Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

The aim of this study is to determine whether structural MRI measures are associated with clinical impairment and progression to a Lewy body disease in patients with idiopathic REM sleep behavior disorder (iRBD). Twenty-seven patients with iRBD in addition to patients with de novo PD and healthy controls were included from the Parkinson's Progression Markers Initiative. Patients with iRBD were followed for up to 3 years. Clinical and MRI measures were compared across groups and the association between clinical features and structural MRI was assessed in iRBD patients. Cox regression analyses were applied to identify risk factors for progressing to a Lewy body disease in iRBD. Our results showed that, at baseline, iRBD patients showed parietal and occipital cortical thinning, compared to controls. They also showed worse motor and non-motor abilities, some of which correlated with motor, frontal or temporal cortical thinning. At follow-up, six (22%) iRBD patients were diagnosed with a Lewy body disorder. These patients showed cortical thinning in frontal, occipital and parietal areas compared to iRBD non-converters. Cortical thinning was a significant predictor for future development of a Lewy body disorder (HR: 0.784; 95% CI: 0.640-0.960; p = 0.02). We conclude that cortical thinning is associated with worse motor and non-motor abilities, and predicts conversion to a Lewy body disorder in iRBD, suggesting it could be used to select candidates for clinical trials to delay the onset of neurodegenerative disease.
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http://dx.doi.org/10.1038/s41531-019-0079-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499806PMC
May 2019
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