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Ferreira D.,Center for Alzheimer Research | Cavallin L.,Karolinska Institutet | Cavallin L.,Karolinska University Hospital | Larsson E.-M.,Uppsala University | And 12 more authors.
Journal of Internal Medicine | Year: 2015

Background: Atrophy in the medial temporal lobe, frontal lobe and posterior cortex can be measured with visual rating scales such as the medial temporal atrophy (MTA), global cortical atrophy - frontal subscale (GCA-F) and posterior atrophy (PA) scales, respectively. However, practical cut-offs are urgently needed, especially now that different presentations of Alzheimer's disease (AD) are included in the revised diagnostic criteria. Aims: The aim of this study was to generate a list of practical cut-offs for the MTA, GCA-F and PA scales, for both diagnosis of AD and determining prognosis in mild cognitive impairment (MCI), and to evaluate the influence of key demographic and clinical factors on these cut-offs. Methods: AddNeuroMed and ADNI cohorts were combined giving a total of 1147 participants (322 patients with AD, 480 patients with MCI and 345 control subjects). The MTA, GCA-F and PA scales were applied and a broad range of cut-offs was evaluated. Results: The MTA scale showed better diagnostic and predictive performances than the GCA-F and PA scales. Age, apolipoprotein E (ApoE) ε4 status and age at disease onset influenced all three scales. For the age ranges 45-64, 65-74, 75-84 and 85-94 years, the following cut-offs should be used. MTA: ≥1.5, ≥1.5, ≥2 and ≥2.5; GCA-F, ≥1, ≥1, ≥1 and ≥1; and PA, ≥1, ≥1, ≥1 and ≥1, respectively, with an adjustment for early-onset ApoE ε4 noncarrier AD patients (MTA: ≥2, ≥2, ≥3 and ≥3; and GCA-F: ≥1, ≥1, ≥2 and ≥2, respectively). Conclusions: If successfully validated in clinical settings, the list of practical cut-offs proposed here might be useful in clinical practice. Their use might also (i) promote research on atrophy subtypes, (ii) increase the understanding of different presentations of AD, (iii) improve diagnosis and prognosis and (iv) aid population selection and enrichment for clinical trials. © 2015 The Association for the Publication of the Journal of Internal Medicine. Source


Lebedeva A.,Karolinska Institutet | Westman E.,Karolinska Institutet | Lebedev A.V.,University of Stavanger | Li X.,Karolinska Institutet | And 7 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2014

Objective: To examine neuroanatomical changes associated with depressive symptoms in Alzheimer's disease (AD) and the relationship between brain structure and cerebrospinal fluid (CSF) AD biomarkers in depressed and non-depressed patients. Methods: Two independent cohorts were used in this study. The first cohort (KI) was collected from the Memory Clinic at Karolinska University Hospital and consisted of 41 AD patients. The second cohort was selected and downloaded from the Alzheimer's Disease Neuroimaging Initiative database (ADNI) and consisted of 148 patient. Patients underwent medical, neuropsychological assessment, laboratory analyses of CSF, including β amyloid 1-42 (Aβ 42), total τ (t-τ), phosphorylated τ 181 (p-τ) and brain MRI examination. In the KI cohort, depression was assessed using the Cornell Scale for Depression in Dementia, and in the ADNI cohort the Geriatric Depression Scale was applied. 3D T1-weighted MRI images were processed using automated steps for segmentation and surface reconstruction implemented in Freesurfer. General linear model analysis was used as a statistical approach. Results Cortical thinning in AD patients with depressive symptoms compared with those without was observed in the left parietal and temporal brain regions in both cohorts. Negative correlation between cortical thickness and t-τ was greater in depressed compared with non-depressed AD patients in precuneus and parahippocampal cortex. Conclusions Our findings suggest that depressive symptoms in AD patients are associated with cortical thinning in temporal and parietal regions. In addition, our findings suggest that τ protein pathology in these areas may contribute to the development of depressive symptoms in AD. Source


Ferreira D.,Karolinska Institutet | Cavallin L.,Karolinska Institutet | Cavallin L.,Karolinska University Hospital | Granberg T.,Karolinska Institutet | And 14 more authors.
European Radiology | Year: 2016

Objectives: To validate a visual rating scale of frontal atrophy with quantitative imaging and study its association with clinical status, APOE ε4, CSF biomarkers, and cognition. Methods: The AddNeuroMed and ADNI cohorts were combined giving a total of 329 healthy controls, 421 mild cognitive impairment patients, and 286 Alzheimer’s disease (AD) patients. Thirty-four patients with frontotemporal dementia (FTD) were also included. Frontal atrophy was assessed with the frontal sub-scale of the global cortical atrophy scale (GCA-F) on T1-weighted images. Automated imaging markers of cortical volume, thickness, and surface area were evaluated. Manual tracing was also performed. Results: The GCA-F scale reliably reflects frontal atrophy, with orbitofrontal, dorsolateral, and motor cortices being the regions contributing most to the GCA-F ratings. GCA-F primarily reflects reductions in cortical volume and thickness, although it was able to detect reductions in surface area too. The scale showed significant associations with clinical status and cognition. Conclusion: The GCA-F scale may have implications for clinical practice as supportive diagnostic tool for disorders demonstrating predominant frontal atrophy such as FTD and the executive presentation of AD. We believe that GCA-F is feasible for use in clinical routine for the radiological assessment of dementia and other disorders. Key points: • The GCA-F visual rating scale reliably reflects frontal brain atrophy. • Orbitofrontal, dorsolateral, and motor cortices are the most contributing regions. • GCA-F shows significant associations with clinical status and cognition. • GCA-F may be supportive diagnostic tool for disorders demonstrating predominant frontal atrophy. • GCA-F may be feasible for use in radiological routine. © 2015, European Society of Radiology. Source


Orellana C.,Center for Alzheimer Research | Ferreira D.,Center for Alzheimer Research | Muehlboeck J.-S.,Center for Alzheimer Research | Mecocci P.,University of Perugia | And 10 more authors.
Neurodegenerative Diseases | Year: 2016

Background: Global brain atrophy is present in normal aging and different neurodegenerative disorders such as Alzheimer's disease (AD) and is becoming widely used to monitor disease progression. Summary: The brain volume/cerebrospinal fluid index (BV/CSF index) is validated in this study as a measurement of global brain atrophy. We tested the ability of the BV/CSF index to detect global brain atrophy, investigated the influence of confounders, provided normative values and cut-offs for mild, moderate and severe brain atrophy, and studied associations with different outcome variables. A total of 1,009 individuals were included [324 healthy controls, 408 patients with mild cognitive impairment (MCI) and 277 patients with AD]. Magnetic resonance images were segmented using FreeSurfer, and the BV/CSF index was calculated and studied both cross-sectionally and longitudinally (1-year follow-up). Both AD patients and MCI patients who progressed to AD showed greater global brain atrophy compared to stable MCI patients and controls. Atrophy was associated with older age, larger intracranial volume, less education and presence of the ApoE ε4 allele. Significant correlations were found with clinical variables, CSF biomarkers and several cognitive tests. Key Messages: The BV/CSF index may be useful for staging individuals according to the degree of global brain atrophy, and for monitoring disease progression. It also shows potential for predicting clinical changes and for being used in the clinical routine.Background: Effective therap. © 2015 S. Karger AG, Basel. Source


Pereira J.B.,Karolinska Institutet | Cavallin L.,Karolinska Institutet | Cavallin L.,Karolinska University Hospital | Spulber G.,Karolinska Institutet | And 15 more authors.
Journal of Internal Medicine | Year: 2014

Background: Visual assessment of medial temporal lobe atrophy (MTA; range 0-4, from no atrophy to increasing atrophy of the choroid fissure, temporal horns and hippocampus) is a sensitive radiological marker of Alzheimer's disease (AD). One of the critical elements for visual MTA assessment is the cut-off score that determines deviation from normality. Methods: In this study, we assessed the sensitivity and specificity of different MTA cut-off scores to classify control subjects, individuals with mild cognitive impairment (MCI) and AD patients from two large independent cohorts, AddNeuroMed and Alzheimer's Disease Neuroimaging Initiative. Of note, we evaluated the effects of clinical, demographic and genetic variables on the classification performance according to the different cut-offs. Results: A cut-off of ≥1.5 based on the mean MTA scores of both hemispheres showed higher sensitivity in classifying patients with AD (84.5%) and MCI subjects (75.8%) who converted to dementia compared to an age-dependent cut-off. The age-dependent cut-off showed higher specificity or ability to correctly identify control subjects (83.2%) and those with MCI who remained stable (65.5%). Increasing age, early-onset disease and absence of the ApoE ε4 allele had a stronger influence on classifications using the ≥1.5 cut-off. Above 75 years of age, an alternative cut-off of ≥2.0 should be applied to achieve a classification accuracy for both patients with AD and control subjects that is clinically useful. Conclusion: Clinical, demographic and genetic variables can influence the classification of MTA cut-off scores, leading to misdiagnosis in some cases. These variables, in addition to the differential sensitivity and specificity of each cut-off, should be carefully considered when performing visual MTA assessment. © 2013 The Association for the Publication of the Journal of Internal Medicine. Source

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