| 1. |
- Dartora, Caroline, et al.
(författare)
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A deep learning model for brain age prediction using minimally preprocessed T1w images as input
- 2023
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: In the last few years, several models trying to calculate the biological brain age have been proposed based on structural magnetic resonance imaging scans (T1-weighted MRIs, T1w) using multivariate methods and machine learning. We developed and validated a convolutional neural network (CNN)-based biological brain age prediction model that uses one T1w MRI preprocessing step when applying the model to external datasets to simplify implementation and increase accessibility in research settings. Our model only requires rigid image registration to the MNI space, which is an advantage compared to previous methods that require more preprocessing steps, such as feature extraction. Methods: We used a multicohort dataset of cognitively healthy individuals (age range = 32.0–95.7 years) comprising 17,296 MRIs for training and evaluation. We compared our model using hold-out (CNN1) and cross-validation (CNN2–4) approaches. To verify generalisability, we used two external datasets with different populations and MRI scan characteristics to evaluate the model. To demonstrate its usability, we included the external dataset’s images in the cross-validation training (CNN3). To ensure that our model used only the brain signal on the image, we also predicted brain age using skull-stripped images (CNN4). Results: The trained models achieved a mean absolute error of 2.99, 2.67, 2.67, and 3.08 years for CNN1–4, respectively. The model’s performance in the external dataset was in the typical range of mean absolute error (MAE) found in the literature for testing sets. Adding the external dataset to the training set (CNN3), overall, MAE is unaffected, but individual cohort MAE improves (5.63–2.25 years). Salience maps of predictions reveal that periventricular, temporal, and insular regions are the most important for age prediction. Discussion: We provide indicators for using biological (predicted) brain age as a metric for age correction in neuroimaging studies as an alternative to the traditional chronological age. In conclusion, using different approaches, our CNN-based model showed good performance using one T1w brain MRI preprocessing step. The proposed CNN model is made publicly available for the research community to be easily implemented and used to study ageing and age-related disorders.
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| 2. |
- Fiuza, Felipe P., et al.
(författare)
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Aging Alters Daily and Regional Calretinin Neuronal Expression in the Rat Non-image Forming Visual Thalamus
- 2021
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Aging affects the overall physiology, including the image-forming and non-image forming visual systems. Among the components of the latter, the thalamic retinorecipient inter-geniculate leaflet (IGL) and ventral lateral geniculate (vLGN) nucleus conveys light information to subcortical regions, adjusting visuomotor, and circadian functions. It is noteworthy that several visual related cells, such as neuronal subpopulations in the IGL and vLGN are neurochemically characterized by the presence of calcium binding proteins. Calretinin (CR), a representative of such proteins, denotes region-specificity in a temporal manner by variable day-night expression. In parallel, age-related brain dysfunction and neurodegeneration are associated with abnormal intracellular concentrations of calcium. Here, we investigated whether daily changes in the number of CR neurons are a feature of the aged IGL and vLGN in rats. To this end, we perfused rats, ranging from 3 to 24 months of age, within distinct phases of the day, namely zeitgeber times (ZTs). Then, we evaluated CR immunolabeling through design-based stereological cell estimation. We observed distinct daily rhythms of CR expression in the IGL and in both the retinorecipient (vLGNe) and non-retinorecipient (vLGNi) portions of the vLGN. In the ZT 6, the middle of the light phase, the CR cells are reduced with aging in the IGL and vLGNe. In the ZT 12, the transition between light to dark, an age-related CR loss was found in all nuclei. While CR expression predominates in specific spatial domains of vLGN, age-related changes appear not to be restricted at particular portions. No alterations were found in the dark/light transition or in the middle of the dark phase, ZTs 0, and 18, respectively. These results are relevant in the understanding of how aging shifts the phenotype of visual related cells at topographically organized channels of visuomotor and circadian processing.
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| 3. |
- Giannakopoulos, Panteleimon, et al.
(författare)
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Prediction of Subtle Cognitive Decline in Normal Aging : Added Value of Quantitative MRI and PET Imaging
- 2021
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative imaging processing tools have been proposed to improve clinic-radiological correlations but their added value at the initial stages of cognitive decline is still a matter of debate. We performed a longitudinal study in 90 community-dwelling elders with three neuropsychological assessments during a 4.5 year follow-up period, and visual assessment of medial temporal atrophy (MTA), white matter hyperintensities, cortical microbleeds (CMB) as well as amyloid positivity, and presence of abnormal FDG-PET patterns. Quantitative imaging data concerned ROI analysis of MRI volume, amyloid burden, and FDG-PET metabolism in several AD-signature areas. Multiple regression models, likelihood-ratio tests, and areas under the receiver operating characteristic curve (AUC) were used to compare quantitative imaging markers to visual inspection. The presence of more or equal to four CMB at inclusion and slight atrophy of the right MTL at follow-up were the only parameters to be independently related to the worst cognitive score explaining 6% of its variance. This percentage increased to 24.5% when the ROI-defined volume loss in the posterior cingulate cortex, baseline hippocampus volume, and MTL metabolism were also considered. When binary classification of cognition was made, the area under the ROC curve increased from 0.69 for the qualitative to 0.79 for the mixed imaging model. Our data reveal that the inclusion of quantitative imaging data significantly increases the prediction of cognitive changes in elderly controls compared to the single consideration of visual inspection.
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| 4. |
- Haller, Sven, et al.
(författare)
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Automatic MRI volumetry in asymptomatic cases at risk for normal pressure hydrocephalus
- 2023
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- The occurrence of significant Alzheimer's disease (AD) pathology was described in approximately 30% of normal pressure hydrocephalus (NPH) cases, leading to the distinction between neurodegenerative and idiopathic forms of this disorder. Whether or not there is a specific MRI signature of NPH remains a matter of debate. The present study focuses on asymptomatic cases at risk for NPH as defined with automatic machine learning tools and combines automatic MRI assessment of cortical and white matter volumetry, risk of AD (AD-RAI), and brain age gap estimation (BrainAge). Our hypothesis was that brain aging and AD process-independent volumetric changes occur in asymptomatic NPH-positive cases. We explored the volumetric changes in normal aging-sensitive (entorhinal cortex and parahippocampal gyrus/PHG) and AD-signature areas (hippocampus), four control cortical areas (frontal, parietal, occipital, and temporal), and cerebral and cerebellar white matter in 30 asymptomatic cases at risk for NPH (NPH probability >30) compared to 30 NPH-negative cases (NPH probability <5) with preserved cognition. In univariate regression models, NPH positivity was associated with decreased volumes in the hippocampus, parahippocampal gyrus (PHG), and entorhinal cortex bilaterally. The strongest negative association was found in the left hippocampus that persisted when adjusting for AD-RAI and Brain Age values. A combined model including the three parameters explained 36.5% of the variance, left hippocampal volumes, and BrainAge values, which remained independent predictors of the NPH status. Bilateral PHG and entorhinal cortex volumes were negatively associated with NPH-positive status in univariate models but this relationship did not persist when adjusting for BrainAge, the latter remaining the only predictor of the NPH status. We also found a negative association between bilateral cerebral and cerebellar white matter volumes and NPH status that persisted after controlling for AD-RAI or Brain Age values, explaining between 50 and 65% of its variance. These observations support the idea that in cases at risk for NPH, as defined by support vector machine assessment of NPH-related MRI markers, brain aging-related and brain aging and AD-independent volumetric changes coexist. The latter concerns volume loss in restricted hippocampal and white matter areas that could be considered as the MRI signature of idiopathic forms of NPH.
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| 5. |
- Herrmann, François R, et al.
(författare)
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Gray Matter Densities in Limbic Areas and APOE4 Independently Predict Cognitive Decline in Normal Brain Aging
- 2019
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Cross-sectional magnetic resonance imaging (MRI) studies reported significant associations between gray matter (GM) density changes in various limbic and neocortical areas and worst cognitive performances in elderly controls. Longitudinal studies in this field remain scarce and led to conflicting data. We report a clinico-radiological investigation of 380 cognitively preserved individuals who undergo neuropsychological assessment at baseline and after 18 months. All cases were assessed using a continuous cognitive score taking into account the global evolution of neuropsychological performances. The vast majority of Mini Mental State Examination (MMSE) 29 and 30 cases showed equal or worst performance at follow-up due to a ceiling effect. GM densities, white matter hyperintensities and arterial spin labeling (ASL) values were assessed in the hippocampus, amygdala, mesial temporal and parietal cortex at inclusion using 3 Tesla MRI Scans. Florbetapir positron emission tomography (PET) amyloid was available in a representative subsample of 64 cases. Regional amyloid uptake ratios (SUVr), mean cortical SUVr values (mcSUVr) and corresponding z-scores were calculated. Linear regression models were built to explore the association between the continuous cognitive score and imaging variables. The presence of an APOE-epsilon 4 allele was negatively related to the continuous cognitive score. Among the areas studied, significant associations were found between GM densities in the hippocampus and amygdala but not mesial temporal and parietal areas and continuous cognitive score. Neither ASL values, Fazekas score nor mean and regional PET amyloid load was related to the cognitive score. In multivariate models, the presence of APOE-epsilon 4 allele and GM densities in the hippocampus and amygdala were independently associated with worst cognitive evolution at follow-up. Our data support the idea that early GM damage in the hippocampus and amygdala occur long before the emergence of the very first signs of cognitive failure in brain aging.
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| 6. |
- Jamshidnejad-Tosaramandani, Tahereh, et al.
(författare)
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Statins and cognition : Modifying factors and possible underlying mechanisms
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 14
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Forskningsöversikt (refereegranskat)abstract
- Statins are a class of widely prescribed drugs used to reduce low-density lipoprotein cholesterol (LDL-C) and important to prevent cardiovascular diseases (CVD). Most statin users are older adults with CVD, who are also at high risk of cognitive decline. It has been suggested that statins can alter cognitive performance, although their positive or negative effects are still debated. With more than 200 million people on statin therapy worldwide, it is crucial to understand the reasons behind discrepancies in the results of these studies. Here, we review the effects of statins on cognitive function and their association with different etiologies of dementia, and particularly, Alzheimer's disease (AD). First, we summarized the main individual and statin-related factors that could modify the cognitive effects of statins. Second, we proposed the underlying mechanisms for the protective and adverse effects of statins on cognitive performance. Finally, we discussed potential causes of discrepancies between studies and suggested approaches to improve future studies assessing the impact of statins on dementia risk and cognitive function.
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| 7. |
- Lilja-Lund, Otto, et al.
(författare)
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Dual-Task Performance in Older Adults With and Without Idiopathic Normal Pressure Hydrocephalus
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Two of the main features of idiopathic normal pressure hydrocephalus (iNPH) are disturbed gait and cognition. These features are typically investigated separately, but here we combined walking with a cognitive task to investigate if older adults with iNPH were more susceptible to dual-task interference on walking than those without iNPH. In total, 95 individuals from the general population participated in our study. Of these, 20 were classified as Possible iNPH (median [interquartile range, IQR] 80 years [75–82.5]) and 75 as Unlikely iNPH (74 years [72–78]). Conversation, 10-m walking, semantic and phonemic verbal fluency were performed either combined or independently. “Stopping walking while talking” was noted. Pairwise comparisons and multiple logistic regression analyses were used. We found that the Possible iNPH group was older, stopped walking more frequently during the conversation, and had a slower single-task pace. The dual-task pace was slower for both groups. Only single-task walking pace could predict Possible iNPH when adjusted for age. We could establish a dual-task cost on gait performance in this sample of older adults from the general population, but the cost was not exclusive for individuals with Possible iNPH. To further assess the value of dual-task testing in iNPH, including observations of stopping walking while talking, a study of a clinical iNPH material with more severe symptoms would be valuable.
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| 8. |
- Nylander, Ruta, et al.
(författare)
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Small Vessel Disease on Neuroimaging in a 75-Year-Old Cohort (PIVUS) : Comparison With Cognitive and Executive Tests.
- 2018
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Signs of small vessel disease (SVD) are commonly seen on magnetic resonance imaging (MRI) of the brain in cognitively healthy elderly individuals, and the clinical relevance of these are often unclear. We have previously described three different MRI manifestations of SVD as well as cerebral perfusion in a longitudinal study of non-demented 75-year-old subjects. The purpose of the present study was to evaluate the relationship of these findings to cognition and executive function at age 75 and changes after 5 years. Methods: In all, 406 subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study were examined with MRI of the brain at age 75 years. Two-hundred and fifty of the subjects were re-examined 5 years later. White matter hyperintensities (WMHs) and lacunar infarcts (LIs) were assessed on both occasions, but microbleeds (MBs) and perfusion only at age 75. Cognitive function was screened by the Mini Mental State Examination (MMSE). Trail Making Test A and B (TMT-A and TMT-B) were performed at baseline and at follow-up at age 80. Results: At baseline, 93% performed >27 points in the MMSE. The TMT-B at age 75 was significantly related to WMH visual scoring after adjustment for sex, education and cerebrovascular disease risk factors (+80 s (95% CI 0.3-161 s), P < 0.05 for grade 2-3 vs. grade 0). Neither MMSE nor TMT-A was significantly related to WMH scoring. There was no relation between any test performance and WMH volume, white matter volume, number of MBs or brain perfusion at age 75. Subjects who had sustained a new LI (n = 26) showed a greater increase of the time to perform TMT-A at the 5-year follow-up (+25 s vs. +4 s in LI-free subjects, P = 0.003). Changes in MMSE or TMT-A and -B test performance between ages 75 and 80 were not related to changes in WMH scoring or volume during the 5 years follow-up, or to brain perfusion at age 75. Conclusion: In this cognitively healthy community-based population, moderate-severe WMHs and incident LIs on brain MRI in individuals aged 75-80 years were associated with a mild impairment of processing speed and executive function.
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| 9. |
- Steurer, Hanna, et al.
(författare)
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Characterization of Mild and Moderate Dysarthria in Parkinson's Disease : Behavioral Measures and Neural Correlates
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- PurposeAlterations in speech and voice are among the most common symptoms in Parkinson's disease (PD), often resulting in motor speech disorders such as hypokinetic dysarthria. We investigated dysarthria, verbal fluency, executive functions, and global cognitive function in relation to structural and resting-state brain changes in people with PD. MethodsParticipants with mild-moderate PD (n = 83) were recruited within a randomized controlled trial and divided into groups with varying degrees of dysarthria: no dysarthria (noDPD), mild dysarthria (mildDPD), moderate dysarthria (modDPD), and also combined mildDPD and modDPD into one group (totDPD). Voice sound level and dysphonia, verbal fluency, motor symptoms, executive functions, disease severity, global cognition, and neuroimaging were compared between groups. Gray matter volume and intensity of spontaneous brain activity were analyzed. Additionally, regressions between behavioral and neuroimaging data were performed. ResultsThe groups differed significantly in mean voice sound level, dysphonia, and motor symptom severity. Comparing different severity levels of dysarthria to noDPD, groups differed focally in resting-state activity, but not in brain structure. In totDPD, lower scores on semantic verbal fluency, a composite score of executive functions, and global cognition correlated with lower superior temporal gyrus volume. ConclusionThis study shows that severity of dysarthria may be related to underlying structural and resting-state brain alterations in PD as well as behavioral changes. Further, the superior temporal gyrus may play an important role in executive functions, language, and global cognition in people with PD and dysarthria.
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| 10. |
- Uzuegbunam, Bright C., et al.
(författare)
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Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of α-synuclein aggregates (α-syn) in the human brain is an occurrence common to all α-synucleinopathies. Non-invasive detection of these aggregates in a living brain with a target-specific radiotracer is not yet possible. We have recently discovered that the inclusion of a methylenedioxy group in the structure of diarylbisthiazole (DABTA)-based tracers improves binding affinity and selectivity to α-syn. Subsequently, complementary in silico modeling and machine learning (ML) of tracer–protein interactions were employed to predict surface sites and structure–property relations for the binding of the ligands. Based on this observation, we developed a small focused library of DABTAs from which 4-(benzo[d][1,3]dioxol-5-yl)-4′-(3-[18F]fluoro-4-methoxyphenyl)-2,2′-bithiazole [18F]d2, 6-(4′-(3-[18F]fluoro-4-methoxyphenyl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d4, 4-(benzo [d][1,3]dioxol-5-yl)-4′-(6-[18F]fluoropyridin-3-yl)-2,2′-bithiazole [18F]d6, and 6-(4′-(6-[18F]fluoropyridin-3-yl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d8 were selected based on their high binding affinity to α-syn and were further evaluated. Binding assay experiments carried out with the non-radioactive versions of the above tracers d2, d4, d6, and d8 showed high binding affinity of the ligands to α-syn: 1.22, 0.66, 1.21, and 0.10 nM, respectively, as well as excellent selectivity over β-amyloid plaques (Aβ) and microtubular tau aggregates (>200-fold selectivity). To obtain the tracers, their precursors were radiolabeled either via an innovative ruthenium-mediated (SNAr) reaction ([18F]d2 and [18F]d4) or typical SNAr reaction ([18F]d6 and [18F]d8) with moderate-to-high radiochemical yields (13% – 40%), and high molar activity > 60 GBq/μmol. Biodistribution experiments carried out with the tracers in healthy mice revealed that [18F]d2 and [18F]d4 showed suboptimal brain pharmacokinetics: 1.58 and 4.63 %ID/g at 5 min post-injection (p.i.), and 1.93 and 3.86 %ID/g at 60 min p.i., respectively. However, [18F]d6 and [18F]d8 showed improved brain pharmacokinetics: 5.79 and 5.13 %ID/g at 5 min p.i.; 1.75 and 1.07 %ID/g at 60 min p.i.; and 1.04 and 0.58 %ID/g at 120 min p.i., respectively. The brain uptake kinetics of [18F]d6 and [18F]d8 were confirmed in a dynamic PET study. Both tracers also showed no brain radiometabolites at 20 min p.i. in initial in vivo stability experiments carried out in healthy mice. [18F]d8 seems very promising based on its binding properties and in vivo stability, thus encouraging further validation of its usefulness as a radiotracer for the in vivo visualization of α-syn in preclinical and clinical settings. Additionally, in silico and ML-predicted values correlated with the experimental binding affinity of the ligands.
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