Lena Cavallin

Sensitivity and Specificity of Medial Temporal Lobe Visual Ratings and Multivariate Regional MRI Classification in Alzheimer's Disease

Background Visual assessment rating scales for medial temporal lobe (MTL) atrophy have been used by neuroradiologists in clinical practice to aid the diagnosis of Alzheimers disease (AD). Recently multivariate classification methods for magnetic resonance imaging (MRI) data have been suggested as alternative tools. If computerized methods are to be implemented in clinical practice they need to be as good as, or better than experienced neuroradiologists and carefully validated. The aims of this study were: (1) To compare the ability of MTL atrophy visual assessment rating scales, a multivariate MRI classification method and manually measured hippocampal volumes to distinguish between subjects with AD and healthy elderly controls (CTL). (2) To assess how well the three techniques perform when predicting future conversion from mild cognitive impairment (MCI) to AD. Methods High resolution sagittal 3D T1w MP-RAGE datasets were acquired from 75 AD patients, 101 subjects with MCI and 81 CTL from the multi-centre AddNeuroMed study. An automated analysis method was used to generate regional volume and regional cortical thickness measures, providing 57 variables for multivariate analysis (orthogonal partial least squares to latent structures using seven-fold cross-validation). Manual hippocampal measurements were also determined for each subject. Visual rating assessment of MTL atrophy was performed by an experienced neuroradiologist according to the approach of Scheltens et al. Results We found prediction accuracies for distinguishing between AD and CTL of 83% for multivariate classification, 81% for the visual rating assessments and 89% for manual measurements of total hippocampal volume. The three different techniques showed similar accuracy in predicting conversion from MCI to AD at one year follow-up. Conclusion Visual rating assessment of the MTL gave similar prediction accuracy to multivariate classification and manual hippocampal volumes. This suggests a potential future role for computerized methods as a complement to clinical assessment of AD.

Cerebral Microbleeds: Different Prevalence, Topography, and Risk Factors Depending on Dementia Diagnosis—The Karolinska Imaging Dementia Study

MR studies in more than 1500 patients with dementia revealed that 22% had microbleedsthat were predominantly lobar and occipital in cases of Alzheimer disease. Patients with microbleeds were older, male, and hypertensive. Prevalence, location, and risk factors of microbleeds varied depending on dementia diagnosis and may be taken into account when anticoagulating such patients. BACKGROUND AND PURPOSE: Cerebral microbleeds are thought to represent cerebral amyloid angiopathy when in lobar regions of the brain and hypertensive arteriopathy when in deep and infratentorial locations. By studying cerebral microbleeds, their topography, and risk factors, we aimed to gain an insight into the vascular and amyloid pathology of dementia diagnoses and increase the understanding of cerebral microbleeds in dementia. MATERIALS AND METHODS: We analyzed 1504 patients (53% women; mean age, 63 ± 10 years; 10 different dementia diagnoses) in this study. All patients underwent MR imaging as part of the dementia investigation, and all their clinical parameters were recorded. RESULTS: Among the 1504 patients with dementia, 22% had cerebral microbleeds. Cerebral microbleed topography was predominantly lobar (P = .01) and occipital (P = .007) in Alzheimer disease. Patients with cerebral microbleeds were significantly older (P < .001), were more frequently male (P < .001), had lower cognitive scores (P = .006), and more often had hypertension (P < .001). Risk factors for cerebral microbleeds varied depending on the dementia diagnosis. Odds ratios for having cerebral microbleeds increased with the number of risk factors (hypertension, hyperlipidemia, diabetes, male sex, and age 65 and older) in the whole patient group and increased differently in the separate dementia diagnoses. CONCLUSIONS: Prevalence, topography, and risk factors of cerebral microbleeds vary depending on the dementia diagnosis and reflect the inherent pathology of different dementia diagnoses. Because cerebral microbleeds are seen as possible predictors of intracerebral hemorrhage, their increasing prevalence with an increasing number of risk factors, as shown in our study, may require taking the number of risk factors into account when deciding on anticoagulant therapy in dementia.

Practical cut-offs for visual rating scales of medial temporal, frontal and posterior atrophy in Alzheimer's disease and mild cognitive impairment

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 Alzheimers disease (AD) are included in the revised diagnostic criteria.

SWI or T2*: Which MRI Sequence to Use in the Detection of Cerebral Microbleeds? The Karolinska Imaging Dementia Study

The prevalence of cerebral microbleeds was evaluated in 246 patients using T2* and SWI. Microbleeds were detected in 21% by SWI vs. 17% by T2* imaging. SWI performed well with both thin and thick sections. Thus, SWI is better than T2* for this purpose and robust enough to permit comparison across studies. BACKGROUND AND PURPOSE: Cerebral microbleeds are thought to have potentially important clinical implications in dementia and stroke. However, the use of both T2* and SWI MR imaging sequences for microbleed detection has complicated the cross-comparison of study results. We aimed to determine the impact of microbleed sequences on microbleed detection and associated clinical parameters. MATERIALS AND METHODS: Patients from our memory clinic (n = 246; 53% female; mean age, 62) prospectively underwent 3T MR imaging, with conventional thick-section T2*, thick-section SWI, and conventional thin-section SWI. Microbleeds were assessed separately on thick-section SWI, thin-section SWI, and T2* by 3 raters, with varying neuroradiologic experience. Clinical and radiologic parameters from the dementia investigation were analyzed in association with the number of microbleeds in negative binomial regression analyses. RESULTS: Prevalence and number of microbleeds were higher on thick-/thin-section SWI (20/21%) compared with T2*(17%). There was no difference in microbleed prevalence/number between thick- and thin-section SWI. Interrater agreement was excellent for all raters and sequences. Univariate comparisons of clinical parameters between patients with and without microbleeds yielded no difference across sequences. In the regression analysis, only minor differences in clinical associations with the number of microbleeds were noted across sequences. CONCLUSIONS: Due to the increased detection of microbleeds, we recommend SWI as the sequence of choice in microbleed detection. Microbleeds and their association with clinical parameters are robust to the effects of varying MR imaging sequences, suggesting that comparison of results across studies is possible, despite differing microbleed sequences.

Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut-offs.

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 Alzheimers disease (AD). One of the critical elements for visual MTA assessment is the cut‐off score that determines deviation from normality.

Lack of accuracy for the proposed 'Dubois criteria' in Alzheimer's disease: a validation study from the Swedish brain power initiative.

Background/Aims: Our purpose was to investigate whether the new research criteria for Alzheimer’s disease proposed in 2007 by Dubois et al. are valid in a naturalistic memory clinic sample. Method: Retrospective diagnostic analyses were carried out to compare the traditional diagnostic criteria for dementia with the new criteria suggested by Dubois et al. No patient had gone through all procedures postulated as additional features in the proposed new Dubois criteria. Material: Two independent experienced geriatricians re-examined 150 complete patients’ records. The study physicians were blinded to any of the results of the core and additional features suggested by Dubois et al. to avoid circular diagnostic bias. Results:Among our 96 patients with a clinical diagnosis of subjective cognitive impairment and/or mild cognitive impairment, 2 of the patients with subjective cognitive impairment and 5 patients with mild cognitive impairment would classify as pre-dementia Alzheimer’s disease according to the Dubois criteria. In our 23 Alzheimer patients diagnosed clinically, only 12 of the cases fulfilled the criteria for Alzheimer’s disease suggested by Dubois et al. Interpretation: The proposed new criteria for Alzheimer’s disease are valid in 55% of our patients clinically diagnosed as having full-blown Alzheimer dementia. Additionally, 7.3% ‘true’ Alzheimer cases will be identified in a group of 96 clinically non-demented patients. Our results show that there is a large heterogeneity in a clinical naturalistic sample of patients with an Alzheimer phenotype. Conclusion: There is a need to further validate the currently existing biomarkers in large unselected samples and avoid the pitfall of workup bias and circular diagnostic processes. Additionally, valid age-specific cut-off values for the diagnostic markers in question have to be defined.

Comparison between visual assessment of MTA and hippocampal volumes in an elderly, non-demented population.

Background It is important to have a replicable easy method for monitoring atrophy progression in Alzheimers disease. Volumetric methods for calculating hippocampal volume are time-consuming and commonly used in research. Visual assessments of medial temporal lobe atrophy (vaMTA) is a rapid method for clinical use. This method has not been tested in a large non-demented population in comparison with volumetry mesurements. Since hippocampal volume decreases with time even in normal aging there is also a need to study the normal age differences of medial temporal lobe atrophy. Purpose To compare visual assessment of medial temporal lobe atrophy (vaMTA) with hippocampal volume in a healthy, non-demented elderly population. To describe normal ageing using vaMTA. Material and Methods Non-demented individuals aged 60, 66, 72, 78, 81, 84, and ≥87 years old were recruited from the Swedish National study on Ageing and Care in Kungsholmen (SNAC-K), Sweden. Standard magnetic resonance imaging (MRI) scans, vaMTA, and calculations of hippocampal volumes were performed in 544 subjects. Results Significant correlation (rs = −0.32, P < 0.001, sin; and rs = −0.26, P < 0.001, dx) was found between hippocampal volume measurements and vaMTA. In normal ageing, almost 95% of ≤66-year-olds had a medial temporal lobe atrophy (MTA) score ≤1, with possible scores ranging from 0 to 4. Subjects aged 72, 78, and 81 years scored ≤2, while the two oldest age groups had scores ≤3. Conclusion There was a highly significant correlation between volumetric measurements of the hippocampus and MTA scoring. In normal ageing, there is increasing MTA score. For non-demented elderly individuals ≤70 years, an MTA score of 0–1 may be considered normal, compared with MTA ≤2 for 70–80-years and MTA 3 for >80-year-old individuals.

Overtime reliability of medial temporal lobe atrophy rating in a clinical setting

Background Medial temporal lobe atrophy (MTA) is one of the first magnetic resonance imaging (MRI) signs in patients with Alzheimers disease (AD) and used as a measure of disease progression. Visual assessment of MTA is easy to perform but the reliability of MTA rating over time has not been studied. Purpose To investigate what happens to the MTA rating scores if two radiologists rate the same MRI scans six times over a period of 1 year. Material and Methods One hundred outpatients were included in this study. All patients underwent MRI with a protocol and sequences used for geriatric patients, according to local clinical standards. One neuroradiologist and one general radiologist independently of each other performed retrospective visual assessments of MTA six times, using the same scans, over a period of 1 year. Results Intra-rater kappa varied between κ 0.65 and 0.84 for the neuroradiologist and κ 0.38 and 0.74 for the general radiologist. Intra-rater weighted kappa (wκ) values showed almost perfect agreement for both investigators (wκ 0.83–0.94). Inter-rater reliability showed fair to moderate agreement, with the kappa value varying from κ 0.29 to 0.48 and weighted kappa values ranging from wκ 0.72 to 0.84. There was a statistically significant difference in rating between the two investigators. Conclusion Visual assessment of MTA repeated over time has a high grade of reproducibility when performed by an experienced investigator. The reproducibility drops when assessment is rarely performed. Inter-rater reliability is low when two investigators not working together are compared.

Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer’s disease and mild cognitive impairment (p < 0.05). CSF/serum albumin ratios were high with multiple CMBs (p < 0.001), reflecting accompanying blood–brain barrier dysfunction. T-tau and P-tau levels were lower in Alzheimer’s patients with multiple CMBs when compared to zero CMBs, but did not change in the rest of the cohort. White matter hyperintensities were associated with low Aβ42 in the whole cohort and Alzheimer’s disease (p < 0.05). Aβ42 is the routine CSF-biomarker mainly associated with CMBs in cognitive impairment, and there is an accumulative effect with increasing number of CMBs.

Cortical superficial siderosis: Prevalence and biomarker profile in a memory clinic population

Objective: To gain further insight into cortical superficial siderosis (cSS), a new hemorrhagic neuroimaging marker of cerebral amyloid angiopathy (CAA), and to investigate the clinical, neuroimaging, genetic, and CSF biomarker profile of cSS in a large, consecutive memory clinic series. Methods: We included 1,504 memory clinic patients undergoing dementia investigation including a brain MRI in our center. Routine CSF biomarker analysis was performed in 1,039 patients and APOE genotyping in 520 patients. MRIs were systematically evaluated for presumed marker of small vessel disease: cSS, cerebral microbleeds, enlarged perivascular spaces, white matter hyperintensities, and lacunes. Results: cSS was detected in 40 patients (2.7%; 95% confidence interval [CI] 1.9–3.6); cSS was focal in 33 cases (2.2%; 95% CI 1.5–3.1) and disseminated in 7 (0.5%; 95% CI 0.2–1). Vascular dementia had the highest cSS prevalence (13%; 95% CI 5.4–24.9), followed by Alzheimer disease (5%; 95% CI 3.1–7.5). The most commonly affected area was the occipital lobe (70%; 95% CI 53.5–83.4). cSS was associated with lobar cerebral microbleeds (odds ratio [OR] 7.9; 95% CI 3.4–18.1; p < 0.001), high-degree centrum semiovale perivascular spaces (OR 1.7; 95% CI 1.2–2.6; p = 0.008), and white matter hyperintensities (OR 1.5; 95% CI 1.0–2.2; p = 0.062). APOE ε4/4 genotype was more common in cSS cases compared to those without. CSF β-amyloid 42 was lower in patients with cSS (coefficient −0.09; 95% CI −0.15 to −0.03; p = 0.004). Conclusions: Our large series of memory clinic patients provides evidence that cSS is related to cerebrovascular disease and may be a manifestation of severe CAA, even in patients without intracerebral hemorrhage.