Inter-modality assessment of medial temporal lobe atrophy in a non-demented population: application of a visual rating scale template across radiologists with varying clinical experience

Objectives To assess inter-modality agreement and accuracy for medial temporal lobe atrophy (MTA) ratings across radiologists with varying clinical experience in a non-demented population. Methods Four raters (two junior radiologists and two senior neuroradiologists) rated MTA on CT and MRI scans using Scheltens’ MTA scale. Ratings were compared to a consensus rating by two experienced neuroradiologists for estimation of true positive and negative rates (TPR and TNR) and over- and underestimation of MTA. Inter-modality agreement expressed as Cohen’s κ (dichotomized data), Cohen’s κw, and two-way mixed, single measures, consistency ICC (ordinal data) were determined. Adequate agreement was defined as κ/κw ≥ 0.80 and ICC ≥ 0.80 (significance level at 95% CI ≥ 0.65). Results Forty-nine subjects (median age 72 years, 27% abnormal MTA) with cognitive impairment were included. Only junior radiologists achieved adequate agreement expressed as Cohen’s κ. All raters achieved adequate agreement expressed as Cohen’s κw and ICC. True positive rates varied from 69 to 100% and TNR varied from 85 to 100%. No under- or overestimation of MTA was observed. Ratings did not differ between radiologists. Conclusion We conclude that radiologists with varying experience achieve adequate inter-modality agreement and similar accuracy when Scheltens’ MTA scale is used to rate MTA on a non-demented population. However, TPR varied between radiologists which could be attributed to rating style differences. Key Points • Radiologists with varying experience achieve adequate inter-modality agreement with similar accuracy when Scheltens’ MTA scale is used to rate MTA on a non-demented population. • Differences in rating styles might affect accuracy, this was most evident for senior neuroradiologists, and only junior radiologists achieved adequate agreement on dichotomized (abnormal/normal) ratings. • The use of an MTA scale template might compensate for varying clinical experience which could make it applicable for clinical use.

Validity and reliability of the medial temporal lobe atrophy scale in a memory clinic population

Background Visual rating of medial temporal lobe atrophy (MTA) is often performed in conjunction with dementia workup. Most prior studies involved patients with known or probable Alzheimer’s disease (AD). This study investigated the validity and reliability of MTA in a memory clinic population. Methods MTA was rated in 752 MRI examinations, of which 105 were performed in cognitively healthy participants (CH), 184 in participants with subjective cognitive impairment, 249 in subjects with mild cognitive impairment, and 214 in patients with dementia, including AD, subcortical vascular dementia and mixed dementia. Hippocampal volumes, measured manually or using FreeSurfer, were available in the majority of cases. Intra- and interrater reliability was tested using Cohen’s weighted kappa. Correlation between MTA and quantitative hippocampal measurements was ascertained with Spearman’s rank correlation coefficient. Moreover, diagnostic ability of MTA was assessed with receiver operating characteristic (ROC) analysis and suitable, age-dependent MTA thresholds were determined. Results Rater agreement was moderate to substantial. MTA correlation with quantitative volumetric methods ranged from -0.20 (p< 0.05) to -0.68 (p < 0.001) depending on the quantitative method used. Both MTA and FreeSurfer are able to distinguish dementia subgroups from CH. Suggested age-dependent MTA thresholds are 1 for the age group below 75 years and 1.5 for the age group 75 years and older. Conclusions MTA can be considered a valid marker of medial temporal lobe atrophy and may thus be valuable in the assessment of patients with cognitive impairment, even in a heterogeneous patient population.

Severity of Lesions Involving the Cortical Cholinergic Pathways May Be Associated With Cognitive Impairment in Subacute Ischemic Stroke

Purpose: Impairment of cortical cholinergic pathways (CCP) is an important risk factor for chronic vascular cognitive impairment. However, this phenomenon has rarely been studied in post-stroke cognitive impairment (PSCI). We investigated the relationship between PSCI and CCP lesions assessed by structural magnetic resonance imaging (MRI).Patients and methods: We prospectively enrolled 103 patients within 7 days of ischemic stroke onset. CCP was measured by the cholinergic pathways hyperintensities scale (CHIPS), which semiquantitatively grades MR lesions strategically located on the CCP identified in human brains. We also measured other MRI parameters, including the location and volumes of acute infarcts, cerebral microbleeds, medial temporal lobe atrophy, and white matter lesions. Neuropsychological assessments were performed using the 60-min modified vascular dementia battery (VDB) at 3 months after the index stroke, and PSCI was defined according to VDB as well as ADL.Results: Of all 103 patients, 69 men (67.0%) and 34 women (33.0%) with a mean age of 57.22 ± 12.95 years, 55 patients (53.4%) were judged to have PSCI at 3 months, including 43 (41.7%) patients with PSCI-no dementia and 12 (11.7%) patients with poststroke dementia. According to the VBD assessment, the most commonly impaired cognitive domain was visuomotor speed (27.2%) followed by verbal memory (25.2%). Univariate analysis showed that patients with PSCI were older; had higher informant questionnaire on cognitive decline in the elderly (IQCODE) scores; had more frequent previous stroke history and atrial fibrillation; and had higher CHIPS scores, more severe white matter lesions, and medial temporal lobe atrophy. PSCI patients also had higher depression scores at 3 months. In the multivariate regression analysis, age, IQCODE score, CHIPS score, and Hamilton depression rating scale score were independent predictors of PSCI. Ordinal regression analysis for risk factors of poor functional outcomes revealed that IQCODE scores and cognitive function status were related to mRS score at 3 months after stroke.Conclusion: In patients with early subacute ischemic stroke, the severity of lesions involving the CCP may be associated with cognitive impairment at 3 months.Clinical Trial Registration: Chinese Clinical Trial Registry, identifier: ChiCTR1800014982.

Serum BDNF as a Potential Biomarker of Alzheimer's Disease: Verification Through Assessment of Serum, Cerebrospinal Fluid, and Medial Temporal Lobe Atrophy

There is an urgent need to establish blood biomarkers for Alzheimer's disease (AD). Although it has been speculated that brain-derived neurotrophic factor (BDNF) is associated with AD, whether it can be used as a blood biomarker has yet to be determined. We used serum, cerebrospinal fluid (CSF), and medial temporal lobe atrophy from patients with AD to evaluate the association of BDNF with AD and assess its severity. For the blood analysis, 66 participants [21 normal controls (NCs) with normal cognitive function, 22 patients with mild cognitive impairment (MCI) due to AD, and 23 patients with AD] were included. For the CSF analysis, 30 participants were included. Magnetic resonance imaging, including a voxel-based specific regional analysis system for AD, and a Mini Mental State Examination were performed. Serum levels of BDNF and CSF levels of amyloid-β42, total tau, and phosphorylated tau were measured using ELISA. Serum BDNF levels were significantly lower in the MCI due to AD group than in the NC group (p = 0.037). Although there was no significant difference in the AD group, there was a downward trend compared to the NC group. Serum BDNF levels were positively correlated with CSF Aβ42 levels (r = 0.49, p = 0.005). There was a significant correlation between serum BDNF levels and medial temporal lobe atrophy. Decreased serum BDNF can potentially be used as a biomarker for early AD detection. Early detection of AD with a less invasive blood test is very beneficial, as it allows for intervention before dementia progresses.

Title Plasma Repressor Element 1-Silencing Transcription Factor Levels Decrease in Patients With Alzheimer's Disease

Background: Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST) was considered as a new therapeutic target for neurodegenerative disorders like Alzheimer’s disease (AD). However, the relationships between AD and REST remain unclear. This study aimed to 1) examine plasma REST levels and REST gene AD patients, and 2) further explore the pathological relationships between REST protein levels and cognition decline in clinic, including medial temporal-lobe atrophy. Methods: Subjects (n=252, mean age 68.95±8.78 years old) were recruited in Beijing, China, and then divided into normal cognition (NC) group (n=89), amnestic mild cognitive impairment (aMCI) group (n=79) and AD group (n=84) according to diagnostic criteria. All subjects received neuropsychological assessments, laboratory tests and neuroimaging scans (MRI) at baseline. Plasma REST protein levels and distribution of the single-nucleotide polymorphisms (SNPs) of REST were compared across the three groups. Correlation between cognitive function, neuro-image and REST level was calculated using multi-linear-regression analysis. medial temporal-lobe atrophy (need to add this method). Results: The plasma REST levels in both NC group (430.30±303.43) and aMCI group (414.27±263.39) were significantly higher than AD group ( NC vs AD, p=0.034; aMCI vs AD, p=0.033). There was no significant difference between NC and aMCI group (p=0.948). There was no significant difference among three groups on the distribution of the genotype distribution of Rs2227902 and Rs3976529 of REST gene. The REST level was correlated to left medial temporal-lobe atrophy index (r=0.306, p=0.023). After 6-month follow up, the REST level in NC group was positively related to the change scores of mini-mental state examination scale (MMSE) (r=0.289, p=0.02). Conclusion: Plasma REST protein declines in AD patients, which also associated with memory impairment and left temporal-lobe atrophy, which may have potential value for clinical diagnosis of AD.